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Inceu, A.; Neag, M.; Craciun, A.; Buzoianu, A. Gut Molecules and Cardiovascular Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/41483 (accessed on 22 December 2025).
Inceu A, Neag M, Craciun A, Buzoianu A. Gut Molecules and Cardiovascular Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/41483. Accessed December 22, 2025.
Inceu, Andreea-Ioana, Maria-Adriana Neag, Anca-Elena Craciun, Anca-Dana Buzoianu. "Gut Molecules and Cardiovascular Diseases" Encyclopedia, https://encyclopedia.pub/entry/41483 (accessed December 22, 2025).
Inceu, A., Neag, M., Craciun, A., & Buzoianu, A. (2023, February 21). Gut Molecules and Cardiovascular Diseases. In Encyclopedia. https://encyclopedia.pub/entry/41483
Inceu, Andreea-Ioana, et al. "Gut Molecules and Cardiovascular Diseases." Encyclopedia. Web. 21 February, 2023.
Gut Molecules and Cardiovascular Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24043385

Atherosclerotic cardiovascular disease is the most common cause of morbidity and mortality worldwide. Diabetes mellitus increases cardiovascular risk. Heart failure and atrial fibrillation are associated comorbidities that share the main cardiovascular risk factors. The use of incretin-based therapies promoted the idea that activation of alternative signaling pathways is effective in reducing the risk of atherosclerosis and heart failure. Gut-derived molecules, gut hormones, and gut microbiota metabolites showed both positive and detrimental effects in cardiometabolic disorders. Although inflammation plays a key role in cardiometabolic disorders, additional intracellular signaling pathways are involved and could explain the observed effects. 

gut hormones gut microbiota atherosclerosis heart failure atrial fibrillation

1. Atherosclerosis

1.1. Gut Peptides

  • GLP-1. GIP
Atherogenesis is a sequential process that involves many molecules and cells that interfere bidirectionally. Lesion initiation and growth involve the activation of endothelial cells (ECs) that cause the recruitment of monocytes, macrophage differentiation, and foam cell development. Advanced lesions include several additional mechanisms: smooth muscle cell (SMC) transition from a contractile state into a proliferative one, SMC migration into the intima and secretion of an extracellular matrix to form a fibrous cap, T and B cell activation induced by antigens in the atherosclerotic lesion and lesions calcification. Atherosclerotic plaques contain a large amount of cholesterol and a necrotic core. The necrotic core consists of foam cells, collagen, and SMC and is the result of the dysfunctional macrophages’ death clearance mechanisms, such as apoptosis–efferocytosis, necrosis, ferroptosis, autophagy, and pyroptosis. Vulnerable atherosclerotic plaques, prone to rupture, are characterized by degradation of the plaque-stabilizing extracellular matrix, reducing the fibrous cap thickness, neoangiogenesis, intraplaque hemorrhage, and activation of inflammatory mechanisms [1].
GLP-1, GIP, and incretins-based therapies may improve the atherosclerotic burden through the regulation of steps involved in atherosclerosis progression. In animal studies, GLP-1 and GIP have been associated with improved endothelial function, reduced atherosclerotic lesions formation by decreasing local inflammation and lipids infiltration, and a stable phenotype of the atherosclerotic plaque [2]. The main processes in atherosclerotic plaque development mediated by incretins are summarized in Figure 1.
Figure 1. The effects of incretins in atherogenesis. NO: nitric oxide; ROS: reactive oxygen species; EC: endothelial cells; SMC: smooth muscle cells; MMP: metalloproteinase; EPCs: endothelial progenitor cells.
Endothelial dysfunction involves complex pathways and is often regarded as the first step in atherosclerosis development. In diabetic patients, high levels of plasmatic glucose over time can alter the endothelium properties. GLP-1 improves endothelial function via increasing nitric oxide (NO), enhancing vasorelaxation, and decreasing reactive oxygen species (ROS) generated during oxidative stress and adhesion molecules induced in hyperglycemic states in the vascular wall [3]. Higher levels of NO occur due to the activation of endothelial nitric oxide synthase (eNOS) expression in cAMP-dependent manner in hyperglycemia conditions [4]. GLP-1 attenuated the endothelial dysfunction, the excessively stimulated autophagy of endothelial cells, and decreased the levels of ROS via reducing the phosphorylation of ERK 1/2 and restoring the expression of epigenetic factor histone deacetylase 6 (HDAC6), a key regulator of redox processes regulation [5]. GLP-1 infusion in cardiac microvascular endothelial cells cultured in high glucose conditions decreased oxidative stress generation and reduced the apoptosis index, improving vascular dysfunction in a cAMP/PKA-dependent manner [6]. GLP-1 was demonstrated to be an important regulator of endothelial progenitor cells (EPCs), which are part of the restoration process of endothelial integrity after an injury, enhancing EPCs proliferation and differentiation via vascular endothelial growth factor (VEGF) generation [7]. In an experimental study based on TNF-α stimulation in endothelial cells, exendin-4, a GLP-1R agonist, downregulated NF-κB activity and adhesion molecules expression, indicating an anti-inflammatory role of GLP-1 in endothelial cells [8].
GLP-1 protects against vascular remodeling through inhibition of vascular smooth muscle cell migration and proliferation, a mechanism involving increased mitochondrial activity and mitochondrial fusion and inhibition of dynamin-related protein 1 (DRP1) in a PKA-dependent manner [9]. In an in vitro study over coronary smooth muscle cells stimulated by TNF-α in the context of atherosclerosis, the authors concluded that exendin-4 downregulates the expression of MMPs through inhibition of Akt signaling pathway, suggesting an important role for GLP-1 in atherosclerotic plaque vulnerability [10].
In diabetic Apo E -/- mice, long-term GIP infusion caused a reduction in LDL-induced foam cell production and macrophage-driven atherosclerotic lesions, even though GIPR expression in macrophages was mildly reduced by the diabetic state [11]. The inhibition of foam cell formation by macrophages was based on the suppression of cyclin-dependent kinase 5 (Cdk5)/CD36 pathway, a pathway that has been correlated with LPS-induced inflammation and advanced glycation end products (AGEs)-derived atherosclerosis [12]. In an experimental study, GIP overexpression improved atherosclerotic plaque stability by decreasing macrophage infiltration and increasing collagen content. Treatment with GIP reduced monocyte migration and prevented pro-inflammatory signaling pathways in macrophages activated by endotoxin [13].
DPP-4 inhibitors were reported to have suppressive effects on atherosclerosis development and progression as a response to increased serum levels of GIP and GLP-1. Terasaki M and colleagues showed that administration of vildagliptin, a DPP-4 inhibitor, attenuates atherosclerotic lesion progression and reduced macrophage accumulation and foam cell formation, effects based partially on GIP and GLP-1 pathways. The study also proved that vildagliptin confers atheroprotective effects beyond that of incretins [14]. In a review of preclinical and clinical studies, vildagliptin was associated with vasculo-protective effects: suppression of inflammation and leukocyte adhesion, regulation of lipid metabolism, mediation of vascular tonus, improvement in endothelial dysfunction and antithrombotic properties [15].
Human studies, despite some controversial effects regarding the incretin’s effects in subclinical atherosclerosis, have shown a significant reduction in cardiovascular events using GLP-1 agonists in patients with diabetes mellitus type 2. GLP-1 infusion during hyperglycemia conditions protected against endothelial dysfunction and oxidative stress generated by high serum concentration of glucose, an effect dependent on the level of glycemia [16]. In a randomized study, in sixty-nine patients with type 2 diabetes, treatment with exenatide for 51 weeks resulted in a significant decrease in oxidative stress markers, malondialdehyde (MDA), oxidized low-density lipoprotein (ox-LDL), and postprandial glycemia and lipidaemia as compared to insulin treatment [17]. In a randomized-controlled trial, exenatide treatment for 52 weeks reduced subclinical atherosclerosis, as assessed by the carotid-intima media thickness (CIMT), and lipid metabolism markers in patients with type 2 diabetes mellitus [18]. A meta-analysis of randomized placebo-controlled cardiovascular outcome trials assessing GLP-1 receptor agonists in patients with type 2 diabetes mellitus, including 56,004 patients with and without established cardiovascular disease, showed a 12% decrease in the primary composite endpoint regarding major adverse cardiovascular events, including cardiovascular mortality, non-fatal MI and non-fatal stroke. Treatment with GLP-1 R agonists reduced the risk of CV and all-cause mortality, fatal and non-fatal stroke, and heart failure hospitalization [19]. A possible mechanism responsible for this observation is the reduction in atherothrombotic events by the GLP-1 agonists. In an in vitro and ex vivo study, exenatide inhibited platelet aggregation induced by thrombin, ADP, or collagen and reduced the thrombus growth, effects based on the GLP-1R signaling [20]. DPP-4 inhibition and the former substrate, the intact form of GLP-1, GLP-1(7–36), also suppressed platelet aggregation and thrombus expansion under physiological flow conditions, but without the involvement of GLP-1R on the platelets [21].
  • Ghrelin
Ghrelin demonstrated positive effects regarding the cardiovascular atherosclerotic disease. In a long-term 19-year follow-up, high ghrelin plasmatic concentrations were associated with protection against coronary heart disease and the C/C variant of the ghrelin promoter was a protective variant in hypertensive subjects [22]. Des-acylated ghrelin was negatively associated with subclinical atherosclerosis in middle-aged women with metabolic syndrome, as assessed by carotid artery intima-media thickness, suggesting gender-specific effects of the des-acylated ghrelin in the development of atherosclerosis [23].
In experimental studies, ghrelin exhibited atheroprotective properties: inhibition of endoplasmic reticulum stress in endothelial cells [24], stimulation of NO synthase in the endothelium via PI3k/Akt/eNOS pathway [25], and consecutive improvement in the endothelial function [26], a decrease in inflammatory reaction and oxidative stress induced by oxLDL [27], attenuation of vascular calcification in a 5’ adenosine monophosphate-activated protein kinase (AMPK)-dependent manner and consecutive autophagy upregulation [28]. Moreover, unacylated ghrelin revealed anti-atherosclerotic effects through regulation of oxidative stress in endothelial cells and decrease in adhesion molecules and inflammatory cells via overexpression of miR-126, an important regulator of vascular inflammation, as well as induction of superoxide dismutase-2 (SOD-2) and mediation of sirtuin 1 (SIRT1) expression, defenders of oxidative stress injury [29], and inhibition of lipid accumulation within the vascular wall [30].
The uncontrolled inflammatory reaction and pro-atherogenic processes increase the risk of plaque rupture and thrombosis. In an animal model of atherosclerosis, ghrelin treatment inhibited atherosclerosis progression and increased the stability of the atherosclerotic plaque via a decrease in neo-vessel formation, MMPs activity, macrophage content, and inflammation markers within the lesion [31]. Ghrelin receptor (GHS-R1) deficiency produced an unstable phenotype of the atherosclerotic lesion, increasing the expression of adhesion molecules and cytokines and reducing the smooth muscle cell content [32].
Following the beneficial observed effects in atherosclerosis development and progression, ghrelin was suggested to exert protective action against in-stent restenosis. The described mechanisms were similar to the anti-atherosclerotic properties: reduction in inflammation, inhibition of vascular smooth muscle cell proliferation and migration in a cAMP/PKA dependent manner, amelioration of endothelial dysfunction via endothelial cell proliferation and eNOS modulation, and inhibition of platelet aggregation and thrombosis [33].
Ghrelin has additional roles in improving angiogenesis in ischemic conditions. In a MI model in diabetic rats, ghrelin improved left ventricular contractility and microvascular density reduced the infarct size, and ameliorated angiogenesis, through GHS-R1a-mediated AMPK/eNOS signaling pathways and upregulation of vascular endothelial growth factor (VEGF), Hypoxia-inducible factor 1-alpha (HIF1-α) and its receptors [34]. In a mouse model of critical limb ischemia, ghrelin promoted the generation of new capillaries and arterioles, with results based on the reduction in apoptosis and fibrosis via the activation of pro-survival Akt/VEGF/Bcl-2 signaling pathways. The genetic mechanisms were the up-regulation of proangiogenic microRNAs (miR-126 and miR-132) and antifibrotic microRNAs (miR-30a) and the down-regulation of antiangiogenic miRNAs (miR-92a and miR-206) induced by ghrelin [35].

1.2. Gut Microbiota

  • TMAO
Intestinal microbiota plays an important role in atherosclerosis development and progression and modulation of atherosclerotic lesion stability. The intestinal metabolites secreted by the gut microbiota possess different properties that can accelerate or protect against atherosclerosis.
TMAO is involved in all stages of atherosclerosis development through different molecular mechanisms that affect endothelial function, vascular inflammation and calcification, lipid metabolism, and plaque progression [36]. TMAO and its precursor, choline, showed to be independent predictors of cardiovascular diseases in apparently healthy middle-aged subjects [37]. In human studies, TMAO levels were correlated with markers of early atherosclerosis development, such as an increased carotid intima-media thickness, independent of other cardiovascular risk factors, insulin resistance, obesity, or fatty liver [38]. In a linear multiple regression model, TMAO was an independent predictor of carotid atherosclerotic lesions, even after adjusting for the traditional cardiovascular risk factors [39] and in symptomatic patients with peripheral artery disease, TMAO levels predicted the disease severity and the cardiovascular mortality [40]. A meta-analysis of 19 prospective studies which included patients that underwent coronary angiography or patients diagnosed with heart failure, chronic kidney disease, or diabetes mellitus concluded that elevated serum levels of TMAO and its precursors (L-carnitine, choline, or betaine) are correlated with an increased risk for major acute vascular events and cardiovascular mortality, independent of the traditional cardiovascular risk factors [41]. Moreover, γ-butyro-betaine (γBB), an intermediary metabolite that forms in the process of conversion of carnitine to TMAO [42], has been associated with carotid atherosclerosis and a higher risk for cardiovascular mortality [43].
Endothelial dysfunction is a process that affects endothelium properties and structure, often regarded as the first step in atherosclerosis development. TMAO was shown to affect endothelial function through activation of high-mobility group box protein 1 (HMGB1), a pro-inflammatory agent that decreases the expression of proteins involved in cell–cell junctions, resulting in a permeable and dysfunctional endothelium, and further upregulation of TLR4, a pro-inflammatory receptor [44] and pyroptosis of endothelial cells through activation of succinate dehydrogenase complex subunit B (SDHB) that increases ROS levels and impairs mitochondrial function [45]. TMAO decreased the endothelial properties of self-repair after cell injury and increased the monocyte adhesion in a PKC/NF-κB/VCAM-1-dependent manner [46] and activated ROS-thioredoxin-interactive protein (TXNIP) cascade, responsible for the stimulation of NLRP3 inflammasome, the release of pro-inflammatory cytokines and reduction in NO [47]. Moreover, TMAO stimulated the inflammation and oxidative stress reactions in endothelial progenitor cells (EPCs) and showed detrimental effects regarding the functions of tube formation and migration of EPCs in patients with stable angina [48].
The stimulation of vascular inflammation by TMAO includes many signaling cascades associated with atherosclerosis development. TMAO induced a pro-inflammatory environment in the vascular wall and favored the expression of IL-1β, IL-6, TNF-α, NF-κB, MMP9, and NLRP3 and activated oxidative stress cascade. The authors of this study demonstrated that oxidative stress activation is required for TMAO-induced inflammation, and it involves molecular mechanisms, such as the suppression of the AMPK/SIRT1 signaling pathway [49]. In an in vitro study, TMAO induced the inflammatory reaction and the synthesis of ROS and favored the expression of adhesion molecules in vascular smooth muscle cells via nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4)/protein arginine methyltransferase 5 (PRMT5)/NF-κB p65/VCAM-1 signaling cascade [50]. Supplementary studies showed that TMAO could stimulate MAPK/ERK/NF-κB cascade [51] and NLRP3 activation through the SORT3-SOD2-mitochondrial ROS signaling pathway [52] to promote vascular inflammation as an atherogenic condition.
TMAO administration in mice increased the atherosclerotic burden and the lipid content in plasma and altered the bile acid profile. TMAO inhibited bile acid synthesis through activation of small heterodimer partner (SHP) and farnesoid X receptor (FXR) pathway and downregulation of Cyp7a1 expression, suggesting that TMAO-induced atherosclerosis progression is correlated with disturbances in lipid and bile acid metabolism [53]. In an animal model of atherosclerosis, TMAO promoted the formation of foam cells and the progression of atherosclerosis, enhancing macrophage recruitment, and the expression of pro-inflammatory cytokines and adhesion molecules via the CD36/MAPK/JNK signaling pathway [54]. The formation of foam cells in the vascular wall includes a series of molecular events that require macrophage receptors and cholesterol particles. TMAO showed pro-atherogenic effects in the foam cell formation: upregulation of macrophage scavenger receptors, downregulation of exporters involved in reverse cholesterol transport [55], and alteration of the electrostatic properties of the interface between endothelial cells and vascular lumen, affecting the influx/efflux of the cholesterol droplets [56]. Luo T and colleagues showed that TMAO may favor coronary artery disease development, even in well-controlled LDL-c levels, by inducing cholesterol accumulation and vascular inflammation via reducing proline/serine-rich coiled-coil protein 1 (PSRC1) expression. PSRC1 demonstrated anti-atherogenic properties, including the stimulation of reverse cholesterol transport and inhibition of inflammation [57].
Vascular calcification is a process affecting mainly the vascular smooth muscle cells that characterize advanced atherosclerotic lesions. TMAO has been involved in the process of vascular calcification and consecutive atherosclerosis progression. In an in vitro, in vivo, and ex vivo study, TMAO promoted the calcification of smooth muscle cells via activation of genes that regulate osteogenic differentiation, such as Runx2 (Runt-related transcription factor 2) and BMP2 (bone morphogenetic protein-2), and stimulation of NLRP3 inflammasome and NF-κB [58].
In a tandem stenosis animal model, TMAO levels were associated with properties of vulnerable atherosclerotic plaques, such as intraplaque hemorrhage, and markers of inflammation and platelet activation. In the same study, TMAO levels, increased in both healthy and unhealthy diets, were not correlated with the extent of atherosclerosis in either prone to atherosclerosis animal studies or Framingham Heart Study [59]. One possible explanation for the association between TMAO levels and the instability of the atherosclerotic plaque is the impairment of M2 polarization and efferocytosis of macrophagocytes induced by TMAO [60]. TMAO was described as a marker of plaque instability and a predictor of plaque rupture vs. erosion as assessed by OCT in STEMI patients [61] and was correlated with the severity of coronary atherosclerosis in patients presenting with acute coronary syndrome [62]. The pro-thrombotic activity of TMAO occurs due to the increase in calcium release from intracellular stores and enhancement of the platelet activation and responsiveness to different pro-coagulant factors, and consecutive thrombosis potential [63] via phosphorylation of ERK1/2/JNK in platelets [64]. In STEMI patients undergoing PCI, TMAO levels fluctuated during the 4-month follow-up and these changes predicted the infarct size, showing significant association, particularly in patients with impaired renal function, suggesting that TMAO could be involved in the ventricular remodeling [65].
The gut≥–artery interaction proposes additional epigenetic mechanisms involved in TMAO signaling. The authors of one in vitro study suggested that TMAO association with atherosclerosis is related to the modulation of miR-17/92 cluster induced by TMAO, which is responsible for the up-regulation of genes involved in inflammation and pro-thrombotic activity, such as IL-12A and PAI-1, plasminogen activator inhibitor 1 [66]. TMAO was associated with the overexpression of miR-21-5p, a genetic factor related to inflammation, and miR-30c-5p, involved in cholesterol and fatty acid metabolism. The expression of PER2, a target gene of both miR-21 and miR-30c and a circadian rhythm regulator, was decreased after TMAO administration, a disruption that can lead to increased cardiovascular risk [67]. In an animal model of TMAO-driven atherosclerosis, TMAO levels up-regulated the expression of miR-146a-5p, as a regulator of NF-κB-driven inflammation [68]. TMAO activated hepatocytes to secrete exosomes that are taken up by the vascular endothelial cells and suppressed the endothelial function and angiogenesis through inhibition of C-X-C chemokine receptor type 4 (CXCR4) expression [69]. The exacerbation of atherosclerosis produced by TMAO includes a positive feedback loop generated by the up-regulation of lncRNA enriched abundant transcript 1 (NEAT1), a regulator of endothelial cell behavior, and miR-370-3p/signal transducer and activator of transcription 3 (STAT3)/flavin-containing monooxygenase-3 axis (FMO3), a cascade that produces excessive proliferation and decreased apoptosis of human aortic endothelial cells [70].
  • LPS
LPS has been studied as a participant in all steps of atherosclerosis development. In an atherosclerosis-prone animal model, increased LPS levels, as a marker of gut dysbiosis, potentiated the progression of atherosclerotic plaques and promoted the proliferation of vascular smooth muscle cells via osteopontin production by monocytes in an NF-κB dependent manner. Moreover, in patients with carotid atherosclerosis, LPS and osteopontin levels were increased and showed a positive correlation, indicating a relationship between gut dysbiosis and atherogenesis both in humans and animals [71]. In patients with PAD, increased LPS levels were associated with the atherosclerotic burden and markers of oxidative stress activation [72]. Lipoprotein particles carry LPS and 3-hydroxy fatty acids (3OHFAs), the immunogenic part of LPS, by binding to LPS-binding protein. The lipid particles charged with LPS may be transferred into the subendothelial space and produce a pro-inflammatory reaction in the atherosclerotic lesion. Although LPS was detected in all lipoprotein particles, the highest amount was transported by LDL and HDL and the quantity of LPS was higher in VLDL particles, with high variability between the subjects being evidenced [73].
In the endothelial cells, LPS showed pro-inflammatory properties and increased miR-146 and CXCL16 expression, a chemokine and adhesion molecule, via TLR4/NF-κB. MiR-146, a negative regulator of atherosclerosis and inflammation, mediated the CXCL16 expression induced by LPS in a TLR4-dependent manner and controlled the inflammation induced by NF-κB through a negative feedback loop [74]. LPS stimulated the expression of adhesion molecules and pro-inflammatory cytokines in senescent endothelial cells, enhancing the basal inflammation state [75] and activated the pro-inflammatory transcription factor NF-κB through Jumonji domain-containing protein D3 (Jmjd3) expression [76], showing complex inflammatory signals involved in the atherogenesis at the endothelial level.
Macrophages are key players that coordinate inflammation, foam cell formation, smooth muscle cell function, and vascular calcification in atherogenesis. Foam cell formation is dependent on the uptake of LDL and mostly oxidized LDL. LPS activated the expression of scavenger receptors in the macrophages, enhancing the uptake of LDL and foam cell formation in a JAK/STAT-dependent pathway [77]. Another signaling cascade influenced by LPS in the activation of scavenger receptors and following the uptake of LDL was MAPK/ERK. LPS increased the scavenger receptor CD204 expression in a MAPK/ERK-dependent manner, whereas CD36 was activated in an ERK-independent way [78]. The uptake of oxLDL into macrophages through the up-regulation of lectin-like oxLDL receptor-1 (LOX-1) expression was induced by LPS via the ERK1/2 signaling pathway [79]. In an in vitro study, LPS promoted inflammation in the murine macrophages cell line by enhancing the expression of adipophilin, a protein involved in foam cell formation and inflammation, through ERK1/2- peroxisome proliferator-activated receptors (PPAR)-γ pathway [80]. iNOS is a key factor involved in macrophage-driven inflammation that can be up-regulated by LPS via myocardin-related transcription factor A (MRTF-A) by bonding to its promoter [81].
Macrophages apoptosis has a dual role in atherogenesis: it confers beneficial effects during the first steps of atherosclerosis development, but in advanced lesions, macrophages apoptosis increases the necrotic core and the instability of the atherosclerotic plaque that becomes more prone to rupture and subsequent thrombosis. LPS produced macrophage apoptosis through sphingosine-1-phosphate (S1P) up-regulation, consecutive decreased urocortin expression, and activation of cytosolic phospholipase A2 (cPLA2) mediated apoptosis pathway. The activation of lipoprotein-associated phospholipase A2 (Lp-PLA2) and p38 and JNK members of the MAPK superfamily by LPS modulated apoptotic cascade [82]. Macrophages stimulated with LPS showed increased levels of IL-1β, IL-6, TNF-α, NLRP3 inflammasome, and ROS as markers of inflammation and oxidative stress and provided the decreased activity of autophagy and biogenesis of extracellular vesicles (EVs). EVs derived from LPS treatment induced inflammation and oxidative stress activation in smooth muscle cells and produced an osteogenic switch of the vascular smooth muscle cells, promoting microvascular calcification, partially due to the decrease in matrix gla protein, an inhibitor of calcification [83]. However, LPS treatment favored the expression of miR-21 in macrophages, a negative regulator of the TLR-4/NF-κB cascade, as a compensatory mechanism for the lipid accumulation and inflammation disturbances induced by LPS [84]. Yu MH and colleagues studied the effect of LPS stimulation in vascular smooth muscle cells and showed that LPS promoted serum amyloid A1 (SAA1) secretion in a concentration and time-dependent manner and activated a pro-inflammatory cascade that includes SAA1-NOX4/ROS-p38MAPK/NF-κB with the release of IL-1β, IL-6, IL-8, IL-17, TNF-α and MCP-1 [85].

2. Heart Failure

2.1. Gut Peptides

  • GLP-1. GIP
Heart failure pathophysiology relies on multiple processes affecting the structure and function of the heart, such as cardiac ischemia and subsequent myocardial infarction-induced necrosis, hypertrophy, fibrosis, inflammation, cardiomyocytes apoptosis, and electrolyte imbalance causing disturbances in cardiac electrolyte handling, particularly calcium [86]. GLP-1 signaling was associated with multiple beneficial effects in heart failure pathophysiology through systemic and cardiac actions. The systemic effects are related to the mediation of insulin secretion and sensitivity and subsequent glucose and lipid metabolism improvement in the pancreas, liver, and adipose tissue. GLP-1 has direct cytoprotective effects in cardiac cells and atheroprotective effects in vascular cells [87].
Incretin-based therapies have been proved to interact with renin–angiotensin–aldosterone system (RAAS) both in animal and clinical studies, therefore suggesting a connection between classical heart failure pathways and incretins. The mechanisms of RAAS components being influenced by incretins are Angiotensin (Ang) II inhibition, Na+/H+ exchanger isotope 3 (NHE3) modulation, regulation of central nervous system (CNS)-induced RAAS activation, and decrease in AT1/AT2 ratio. GLP-1 is involved in Ang II inhibition through PKA-dependent pathways, direct effect on renal juxtaglomerular cells, inhibition of proximal sodium transport, subsequent modulation of tubule-glomerular feedback, and direct Ang II down-regulation [88]. In a study based on both in vivo and in vitro experiments, GIP infusion suppressed cardiomyocyte hypertrophy and apoptosis and interstitial fibrosis in the ventricular wall induced by Ang II via GIP/GIPR/cAMP/phosphorylated Akt axis. According to these morphological changes, GIP infusion produced the downregulation of TGF-β1 and HIF-1α and inhibited the mRNA expression of B-type natriuretic peptide and TGF-β1, which were upregulated by Ang II in vitro [89]. Liraglutide, a GLP-1 analog, significantly reduced cardiac hypertrophy and fibrosis and improved cardiac function in a non-diabetic animal model of cardiac hypertrophy induced by Ang II or pressure overload by modulation of PI3K/Akt1 and AMPKα signaling [90].
A DPP-4 inhibitor, alogliptin, prevented the contractile dysfunction, ventricular remodeling, and cardiomyocytes apoptosis induced by pressure overload in an animal model of ventricular dysfunction via GLP-1R stimulation of cAMP/PKA/EPAC1 signaling pathway that enhance pro-survival proteins [91]. However, the use of some DPP-4 inhibitors increased the risk of heart failure and worsened the evolution of heart failure in diabetic patients. This is explained by the activation of the sympathetic nervous system and stimulation of β-adrenergic receptors through interference of DPP-4 inhibitors with the degradation of substance P, stromal cell-derived factor 1, and neuropeptide Y, causing cardiac cell apoptosis, through a Ca++/calmodulin-dependent protein kinase II pathway [92].
Arterial hypertension is a common cause of heart failure, particularly for HF with preserved EF. In a spontaneously hypertensive, heart failure-prone (SHHF) animal model, GLP-1 infusion for 3 months resulted in improved survival, reduced cardiomyocyte apoptosis via downregulation of caspase-3, preserved left ventricular function and left ventricular mass index and improved myocardial glucose uptake [93]. GLP-1 intestinal secretion was increased as an adaptive response in a hypertensive heart failure experimental model. Miglitol, an α-glucosidase inhibitor, stimulated GLP-1 production, which improved cardiac dysfunction and prevented cardiac remodeling via GLP-1R/PKA. Miglitol, together with enhanced GLP-1 production, mediated the mitochondrial fusion and function by PKA activation and release of mitochondrial fusion-related proteins, leading to increased ATP content, suggesting that GLP-1 can ameliorate cardiac dysfunction by acting at the mitochondrial level [94].
The effects of incretins in experimental myocardial ischemia as a precursor of heart failure development were evaluated in both animal and clinical studies. In both in vivo and ex vivo models of experimental myocardial ischemic injury, GLP-1(28–36), a GLP-1 metabolite generated by neutral endopeptidase, proved to exert cardioprotective effects regarding ischemic cardiac dysfunction, infarct size, and coronary vascular cells. The mechanisms involved were the activation of soluble adenylyl cyclase (sAC) and increased cAMP/PKA activity in coronary smooth muscle cells and endothelial cells, with the consecutive phosphorylation of endothelial nitric oxide synthase (eNOS). An increased intracellular ATP level was observed due to the GLP-1(28–36) mediation of mitochondrial trifunctional protein-α (MTPα) causing a change in the basal metabolism, from fatty acid oxidation to more efficient glucose oxidation and oxygen-sparing glycolysis and further higher levels of cAMP and ATP, reducing the metabolic oxidative stress [95]. On the contrary, in an animal model of myocardial infarction, selective GIPR inactivation reduced the ventricular injury, improved survival, and increased myocardial triacylglycerol (TAG) content by decreasing hormone-sensitive lipase (HSL) phosphorylation via PKG/ERK pathway, suggesting an adaptive role for GIPR signaling in ischemic conditions [96].
Exenatide, a GLP-1 analog, reduced MI size and prevented MI-induced myocardial remodeling and contractile dysfunction in a porcine model of left circumflex artery ligation and subsequent reperfusion. Exenatide treatment increased the expression of phosphorylated Akt, antiapoptotic protein Bcl-2, and the activity of antioxidant enzymes, such as superoxide dismutase and catalase, and decreased caspase-3 activity, suggesting that GLP-1 signaling mediates apoptosis and oxidative stress following ischemia/reperfusion injury [97]. Treatment with sitagliptin, a DPP-4 inhibitor, in ischemic normoglycemic rats attenuates the high levels of resistin associated with MI via GIP-dependent pathways including Akt/PI3K signaling. GIP infusion decreased resistin levels, an adipokine involved in inflammation and atherosclerosis in a similar way to sitagliptin, suggesting that DPP-4 inhibition produced by sitagliptin provides beneficial effects through the mediation of GIP. Moreover, sitagliptin showed antiarrhythmic effects by mediating sympathetic innervation via the PI3K pathway and nerve growth factor (NGF) expression [98].
Pre-treatment with GLP-1(7–36)amide in patients with ischemic heart disease caused by balloon occlusion protected against LV systolic and diastolic dysfunction and improved the recovery of LV performance during reperfusion, without detectable changes in cardiac glucose metabolism, suggesting an independent mechanism for GLP-1 not related to glucose metabolic effects [99]. Intravenous infusion of GLP-1(7–36)amide improved global and regional function of the left ventricle, assessed by velocity, strain, and strain rate, and improved the post-ischemic myocardial stunning, particularly in ischemic segments, in patients with coronary artery disease and ischemic dysfunction induced by dobutamine stress echocardiography [100].
In diabetic patients, the accumulation of methylglyoxal (MG), a precursor of advanced glycation end products (AGEs) and a source for the synthesis of intracellular AGEs, has been related to the development of diabetic cardiomyopathy. In rat cardio-myoblast cells, MG produced oxidative stress activation, myocyte injury, apoptosis, and mitochondrial dysfunction. GLP-1R stimulation with exendin-4 inhibited these effects through activation of the cAMP/EPAC/PI3K/Akt signaling pathway. Exendin-4 via GLP-1R improved mitochondrial membrane potential and the expression of genes involved in mitochondrial function, suggesting a therapeutical role for GLP-1R stimulation in mitochondrial function and oxidative stress [101]. Calcium disturbances are frequently involved in heart failure pathophysiology. Treatment with exendin-4, as a GLP-1R agonist in a MI animal model, decreased the size of the infarcted myocardium, prevented the dilation of cardiac chambers and the progressive remodeling, improved the systolic function of the heart and suppressed myocyte hypertrophy and fibrosis, effects mediated by the circulating GLP-1 and ventricular GLP-1R. At the molecular level, exendin-4 activated the eNOS/cGMP/PKG pathway and inhibited the Ca2+/calmodulin-dependent kinase II (CaMKII) pathway, improving calcium homeostasis via modulation of the expression of proteins responsible for calcium handling: sarcoplasmic reticulum Ca2+uptake ATPase (SERCA2a), phosphorylated phospholamban (PLB), Cav1.2 and phosphorylated ryanodine receptor (RyR) [102]. Exendine-4 decreased inflammation and interstitial fibrosis in the myocardium following MI, besides the protective effects on cardiac function, chamber size, and cardiomyocyte survival. These effects were associated with the downregulation of gene expression of extracellular matrix remodeling markers and pro-inflammatory cytokines and the modulation of Akt/glycogen synthase kinase 3b (GSK-3b) and Smad 2/3 signaling, pathways involved in the fibroblast-driven remodeling and extracellular matrix turnover [103]. GLP-1(9–36)amide, the inactive form of GLP-1, has been involved in protection against ventricular remodeling following experimentally-induced acute myocardial infarction in mice, improving diastolic parameters via the mediation of macrophages infiltration and extracellular matrix composition [104].
Heart failure with preserved ejection fraction (HFpEF), besides being frequently encountered and diagnosed nowadays, does not have an optimal therapeutical approach. In a rat model of HFpEF, GLP-1 infusion improved survival, ameliorated the parameters of diastolic dysfunction, and reduced left ventricular stiffness and pulmonary congestion. GLP-1 infusion was associated with a shift of cardiac metabolism towards glucose oxidation, suggesting a favorable metabolic mechanism of GLP-1 in diastolic dysfunction [105]. In western-diet-fed mice and diastolic dysfunction, DPP-4 inhibition improved diastolic function and insulin resistance, reduced myocardial oxidative stress and fibrosis, and modulated the endothelial vascular ultrastructure [106], indicating that incretins may provide new therapeutic options for patients with HFpEF.
  • Ghrelin
The beneficial effects of ghrelin administration observed in heart failure studies both on animal and human subjects suggested that ghrelin may play a role as a therapeutic agent in heart failure. The cardioprotective actions regarding cardiac hypertrophy, fibrosis, calcium handling, and cardiac remodeling following ischemic injury demonstrate that ghrelin acts on different pathways in the pathophysiology of both heart failure with preserved and reduced ejection fraction [107]. The molecular mechanisms involved are modulation of autophagy, ionotropic actions, anti-apoptotic and anti-inflammatory pathways activation, and regulation of the autonomic nervous system [108].
In chronic heart failure patients, low ghrelin levels were a marker of increased severity and worse prognosis. Ghrelin levels were independently associated with adverse cardiac events in a multivariate analysis, thus suggesting that ghrelin is a possible new guiding marker in heart failure management [109]. In cachectic patients with chronic heart failure, plasmatic levels of ghrelin were elevated and were positively correlated with serum levels of GH and TNF-α, suggesting a compensatory mechanism activated in conditions of accentuated catabolism in chronic heart failure [110]. Furthermore, patients with dilated cardiomyopathy had lower levels of ghrelin, both acylated and un-acylated, than control subjects, and ghrelin levels were inversely associated with the duration and the left ventricular ejection fraction, proving a complex relationship between ghrelin and heart failure development [111]. These contradictory results may be explained by the differences between the subject with different heart failure stages and diverse causes of heart failure. In advanced stages of heart failure, when the ejection fraction is markedly decreased, the ghrelin/GHS-R axis is altered: ghrelin secretion is impaired and GHS-R1a expression is compensatorily increased [112]. Tissue samples from patients with valvular heart disease with or without coronary artery disease and without reduced LVEF provided evidence for a positive correlation between ghrelin and GHS-R levels in the affected areas and between ghrelin, GSH-R, and BNP and the contractility marker, SERCA2, in the left ventricle. The authors also detected a positive correlation between ghrelin and BNP levels and showed that these two peptides are colocalized in the myocardium, suggesting that in valvular heart disease, in the subclinical stage, the deficiency of endocrine signaling may be an important key factor that drives myocardial dysfunction. The correlation with the contractility marker could imply an adaptive cardioprotective mechanism before decreased EF [113]. The infusion of acyl and des-acyl ghrelin in animals with pacing-induced HF improved the cardiac metabolism and energy balance, leading to enhanced free fatty acid oxidation and reduced glucose oxidation, suggesting that impaired ghrelin’s secretion in advanced stages of heart failure may be responsible for metabolic alterations [114]. In chronic heart failure patients, ghrelin administration increased the ejection fraction of the LV, decreased the LVESV, and improved exercise capacity and muscle wasting [115].
Ghrelin showed cardioprotective actions in the ventricular remodeling after myocardial infarction (MI): improvement in cardiac contractility, enhancement of the antioxidant activity of the myocardium, decrease in inflammation, fibrosis, and apoptosis via multiple signaling axis: activation of Raf-1-MEK1/2-ERK1/2 and consecutive inactivation of pro-apoptotic proteins [116] and/or activation of JAK2/STAT3 and inhibition of STAT1 pathway [117]. After MI, the ventricular remodeling is associated with myocardium fibrosis and ECM turnover, involved in contractility dysfunction, and carries the risk of life-threatening arrhythmias. Ghrelin has proved to exert inhibitory effects on fibrosis after MI via the downregulation of activin A (Act A), a member of the TGF-β superfamily and a pro-fibrotic agent, and consequent adjustment of the imbalance between Act A and its blocker-follistatin (FS) [118], inhibition of endothelial-to-mesenchymal transition, an essential process in myocardium fibrosis initiation, in a GHSR-1a/AMPK/Smad7-dependent manner, disrupting TGF-β1 signaling [119], and modulation of oxidative stress reaction by activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and inhibition of NADPH/ROS pathway [120]. Ghrelin manifested anti-apoptotic effects at the ultra-structural level following MI: preservation of the mitochondrial structure, amelioration of microfilament appearance and organization, increase in the number of endoplasmic reticulum intracellular organelles, and improvement in nucleus structure [121].
After an ischemic injury, cardiac fibrosis and ventricular remodeling exhibit a pro-arrhythmic risk. Ghrelin reduces this risk and improves survival and cardiac function by the preservation of the electrophysiological properties of the cardiomyocytes, regulating the L-type Ca channels and sodium channels, and maintaining the action potential normal amplitude and duration. Moreover, ghrelin inhibited cardiac cell apoptosis in a GHS-R1a/MAPK-dependent manner [122], prevented the loss of connexin-43 within the left ventricle and modulated cardiac autonomic innervation [123] with suppressing effects over cardiac sympathetic nerve activity via vagal afferent fibers [124][125].
Myocardial ischemia/reperfusion (IR) injury provides deleterious effects following reperfusion strategies in acute coronary syndromes. Ghrelin has been involved in the improvement in cardiac function following ischemia/reperfusion by decreasing the infarction area, apoptosis, and inflammatory reaction and ameliorating the oxidative stress via modulation of Toll-like receptors 4 (TLR4)/NLRP3 inflammasome signaling pathways. In cultured cardiomyocytes, ghrelin inhibited the LPS-mediated stimulation of NLRP3, caspase-1, and IL-1β, showing anti-inflammatory properties [126]. The inhibition of pro-inflammatory and apoptosis key players was an effect of ghrelin administration in multiple animal studies of myocardial ischemia/reperfusion injury through activation of different pathways, including inflammatory axes, such as High mobility group box 1 (HMGB1)/TLR4/NF-κB pathway [127][128]. Ghrelin preserved cardiac contractility following IR injury and produced a positive inotropic effect by the maintenance of sarcoplasmic reticulum calcium content and intracellular calcium homeostasis [27]. In a model of myocardial ischemia/reperfusion injury, a bioactive fragment of un-acylated ghrelin-UAG 6–13 showed cardioprotective effects by the decrease in the infarcted area and inflammation markers and improvement in myocardial hemodynamic properties, the effects independent of the GHS-R1a activation [129].
The upregulation of Ang II is a well-known mediated pathway in the development of heart failure. Ghrelin inhibited Ang II-induced myocardial hypertrophy and fibrosis by upregulating PPAR-γ and inhibiting the expression of TGF-β1 and associated downstream proteins [130]. Another mechanism involved in Ang II deleterious effect on heart failure is cardiomyocyte apoptosis. Ghrelin administration reduced the Ang II induced-apoptosis of cultured cells and favored the expression of miR-208, a miRNA family responsible for the modulation of several apoptosis pathways, including caspase, with protective effects against Ang II [131]. The antiapoptotic effect of ghrelin can also be explained by the downregulation of miR-122 and the subsequent overexpression of Sestrin-2, both important regulators of cardiac cell apoptosis [132].
Hypertrophy of the myocardium is an adaptive reaction during heart failure development, but it has negative effects in the long term, with the risk of sudden death. Ghrelin showed beneficial effects in attenuating cardiac hypertrophy and consequent fibrosis, inflammation, and apoptosis and improving autophagy activity via the Ca2+/Calmodulin-dependent protein kinase (CaMKK)/AMPK pathway [133]. The activation of the cholinergic anti-inflammatory pathway was a different mechanism activated by ghrelin that ameliorated cardiac hypertrophy [134].
Metabolic-induced cardiomyopathy is related to numerous cardiovascular risk factor and metabolic dysregulation. Ghrelin protected against obesity-induced cardiomyocytes apoptosis and the pro-inflammatory environment caused by the high-fat diet or palmitic acid by the regulation of lncRNA H19/miR-29/IGF-1 [135] and Homeobox transcript antisense RNA (HOTAIR)/miR-196b/IGF-1 axis [136], novel signaling cascades involved in metabolic cardiac injury. In a type 2 diabetic-induced cardiomyopathy mouse model, infusion with des-acyl ghrelin improved contractile dysfunction, reduced cardiac fibrosis, and enhanced the autophagic signaling via modulation of pro-survival cellular AMPK/ERK1/2 signaling pathways, suggesting a cardioprotective role of des-acyl ghrelin [137].
Doxorubicin, an anthracycline tumor suppressing drug, activates multiple pathways that lead to cardiotoxicity. In doxorubicin-induced cardiomyopathy, ghrelin supplementation improved the cardiac dysfunction, cell viability, survival, suppressed apoptosis, and excessive autophagy induced by doxorubicin through inhibition of oxidative stress, activation of mTOR phosphorylation via AMPK suppression and p38-MAPK stimulation [138].
  • CCK
In clinical studies of heart failure patients, CCK levels predicted mortality in elderly women, suggesting an important role of CCK in cardiovascular risk assessment [139]. In an animal model of myocardial infarction, the upregulation of CCK was correlated with markers of heart failure progression, such as BNP levels, left ventricular end-systolic diameter, ejection fraction, and shortening fraction [140]. However, CCK-8 administration, a sulfated carboxyterminal octapeptide and a major bioactive segment of CCK improved the ventricular function and attenuated myocardial fibrosis and ventricular remodeling in an animal study of myocardial infarction [141]. CCK-8 has been studied as a protective factor against Ang II-induced apoptosis via the CCK-1 receptor and PI3K/Akt signaling pathway [142].

2.2. Gut Microbiota-Derived Products

  • TMAO
TMAO, as a marker of gut dysbiosis, is involved in many steps of heart failure development and carries the potential of being both a predictor and a therapeutic target [143]. TMAO levels, increased in patients with chronic heart failure, were an independent predictor of cardiovascular mortality in the long-term follow-up [144] and were associated with NYHA functional class and ischemic etiology of heart failure [145]. Moreover, serum trimethyl lysine (TML) levels, a TMAO precursor, were associated with the presence and severity of heart failure, suggesting a higher risk for cardiovascular death, re-hospitalization, and all-cause mortality in heart failure patients [146]. In the Biology Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) system, TMAO levels were correlated with mortality and/or rehospitalization, and contrary to BNP levels, TMAO levels have not been reduced by the guideline-recommended pharmacological treatment, noticing that further therapeutic measures need to be considered in heart failure treatment [147]. TMAO serum concentration, increased in symptomatic heart failure patients, did not lower after heart transplant or LVAD implantation and was independent of makers of inflammation, oxidative stress, endotoxemia, or gut microbiota composition after multivariable adjustment. After LVAD implantation or heart transplant, the inflammation biomarkers were reduced, but the oxidative stress and endotoxemia markers were increased, suggesting additional mechanisms to hemodynamic improvement, such as the relationship between gut microbiota and inflammation, to be responsible for the heart failure-associated complications [148]. In patients presenting with heart failure with preserved ejection fraction, in the Developing Imaging and plasma biomarkers in describing Heart Failure with Preserved Ejection Fraction (DIAMONDHFpEF) cohort, TMAO levels, increased in patients with left ventricular filling pressure along with BNP levels, were useful for better risk stratification for long-term mortality, particularly in patients with low levels of BNP [149].
In heart failure, the dysfunctional gut–blood barrier induced by reduced intestinal blood flow, decreased thickness of colonic mucosa, and alterations of the tight junctions’ proteins allow an increased passage of the TMAO precursor, TMA, into the blood and consecutive higher plasmatic levels of TMAO that could explain the observed increased TMAO levels in heart failure patients [150]. However, TMAO can activate pathophysiological cascades involved in heart failure development. In an experimental study of pressure overload-induced heart failure, choline or TMAO administration exacerbated the left ventricular dysfunction, cardiac enlargement, and pulmonary edema, increased the levels of BNP, and exacerbated interstitial and perivascular ventricular fibrosis [151]. TMAO was demonstrated to induce cardiac fibrosis and hypertrophy in a TGF-β1/Smad3-dependent manner [152]. TMAO stimulated cardiac inflammation and fibrosis responsible for the systolic and diastolic dysfunction noticed in mice fed with a Western diet, adding supplementary mechanisms for the hypothesis of the gut microbiota as a part of the development of heart failure [153]. Moreover, TMAO administration showed negative effects regarding cardiac contractility and intracellular calcium handling and reduced the sarcomere fraction of shortening and the maximal rate of shortening and re-lengthening, and prolonged the time needed for the removal of cytosolic calcium. Transmission Electron Microscopy (TEM) images showed that cardiomyocytes exposed to TMAO contained increased glycogen accumulation, a higher number of mitochondria, and paranuclear lipofuscin-like droplets, suggesting an impaired energetic metabolism and protein oxidative damage [154].
However, some studies showed the protective effects of TMAO regarding heart failure development. In male spontaneously hypertensive rats, TMAO administration in low doses improved cardiac fibrosis, NT-pro BNP levels, and left ventricular end-diastolic pressure, suggesting the beneficial effects of TMAO in pressure overload diastolic dysfunction [155]. In a rat model of right ventricular heart failure, long-term TMAO administration preserved the right ventricular function via improvement in the mitochondrial energy metabolism through fatty acid oxidation and decrease in pyruvate metabolism, showing preconditioning-like metabolic and cardioprotective effects during heart failure initiation [156]. However, in another study, TMAO impaired mitochondrial metabolism by alterations of fatty acid oxidation and pyruvate metabolism, resulting in cardiac energetic disturbances, suggesting that TMAO could have a dual role in cardiac pathophysiology depending on specific conditions [157].
  • LPS
LPS, as a marker of endotoxemia, has been associated with cardiac dysfunction and heart failure development. In patients with chronic heart failure, LPS responder status, related to the potential to secrete TNF-α to increasing doses of LPS, was an independent predictor of mortality after multivariable adjustment [158]. Moreover, in decompensated chronic heart failure, the gut function of active-carrier-mediated transport was reduced due to gut edema. The high serum LPS levels were associated with an increased level of cytokines, suggesting a complex relationship between decompensated heart failure, edema in the gut wall, gut barrier dysfunction, and epithelial disturbances [159].
The inflammatory reaction that drives heart failure progression may be exacerbated by LPS. LPS increased the expression of syndecan-4 via NF-κB, a member of the syndecan superfamily involved in tissue inflammation and wound healing, and the release of cytokines, adhesion molecules, and extracellular matrix remodeling markers to promote immune cell recruitment, immunity activation, and cardiac remodeling [160]. Additional pro-inflammatory pathways influenced by LPS are the upregulation of miR-203 that inhibits the expression of nuclear factor interleukin-3 (NFIL3) and activates the production of cytokines and pro-apoptotic factors [161], overexpression of long non-coding RNA SRY-Box Transcription Factor 2 (SOX2) overlapping transcript (SOX2OT) and subsequent downregulation of miR-215-5p and release of ICAM-1, as a pro-inflammatory, pro-apoptotic and adhesion molecule [162]. Overexpression of Na+/Ca2+ exchanger 1 (NCX1) induced by LPS promoted cardiac hypertrophy [163]. LPS was involved in cardiomyocyte contractile dysfunction and cardiac calcium handling dysregulation through the decrease in the L-type calcium channels function and oxidative modification of sarcoendoplasmic reticulum Calcium-ATPase (SERCA)- Cys674 sulphonylation [164].
Activation of TLR4 by LPS produced cardiac inflammation, oxidative stress activation, mitochondrial dysfunction, cardiac fibrosis, and cellular apoptosis via SIRT2 inhibition and p53 acetylation [165]. In a rat model of myocardial infarction, the authors demonstrated that after myocardial injury, TLR4 expression is upregulated and the binding capacity of LPS is increased, promoting cardiac inflammation and exacerbation of heart failure [166]. LPS induces cardiac fibrosis through many mechanisms that comprise the upregulation of cardiac fibrosis mediators and enhancement of cellular migration in cardiac fibroblasts via the ERK1/2 signaling pathway [167] and the activation of NADPH oxidase 2 (NOX2) and the downregulation of miR-29 [168].

3. Atrial Fibrillation

Atrial fibrillation is the most common arrhythmia worldwide and is part of the cardiometabolic spectrum of diseases, more frequently encountered in patients with a high cardiovascular risk. The traditional risk factors for atrial fibrillation are coronary artery disease, hypertension, diabetes, heart failure, and obesity, all of them characterized by the description of the gut dysbiosis hypothesis in pathophysiological processes. Therefore, the involvement of gut metabolites in the development and progression of atrial fibrillation has been reviewed. Gut microbiota metabolites, such as TMAO, LPS, secondary bile acids, and indoxyl sulfate have been associated with the remodeling of the autonomic activity, calcium handling mechanisms, the atrial electrical properties and the atrial structure, increasing the risk for atrial fibrillation causing re-entrant substrate and triggered activity [169].
TMAO was associated with the development and progression of atrial fibrillation, independent of other AF traditional risk factors [170]; the enzymes involved in the synthesis of TMA, as a precursor of TMAO, the bacteria genera correlated with these enzymes [171], and the metabolites from choline biochemical cascade, such as choline, betaine, and dimethylglycine [172] were described as part of the association. In an experimental model of AF, TMAO produced atrial electric instability, increased AF inducibility, and aggravated the acute electrical remodeling by enhancement of the cardiac autonomic activity and remodeling and activation of the pro-inflammatory p65 NF-κB signaling pathway, showing a mechanism that may play an important role in the perpetuation of atrial fibrillation [173].
In patients with nonvalvular atrial fibrillation from the ATHERO-AF cohort, circulation levels of LPS were correlated with PCSK9 levels, and the concomitant increased levels were associated with a higher risk of cardiovascular events. Possible mechanisms for this finding were the activation of NADPH oxidase and a prothrombotic effect of LPS produced by the increase in PCSK9 [174]. In the same cohort of patients, LPS levels were correlated with a reduced level of antioxidant enzymes, indicating that LPS could promote impaired antioxidant activity. Patients with higher levels of LPS and reduced antioxidant enzyme glutathione peroxidase 3 had a higher risk of cardiovascular events [175]. LPS and collagen type-1 C-terminal telopeptide (CITP) independently predicted the risk for AF recurrence after radiofrequency ablation. LPS may precipitate atrial fibrillation recurrence through systemic inflammation pathways [176].
In an animal model of age-related atrial fibrillation, high LPS levels, as a marker of a dysfunctional gut barrier, and increased glucose levels produced by impaired glucose tolerance activated the NLRP-3 inflammasome and produced the development of atrial fibrillation via atrial remodeling and fibrosis. The aging process changed the gut microbiota composition and affected the gut barrier integrity, leading to increased gut permeability of LPS into the blood [177]. Moreover, LPS, via stimulation of pro-inflammatory macrophages, increased the incidence of atrial fibrillation, produced atrial electrical remodeling, and reduced the atrial effective refractory period and L-type calcium currents. The interaction between LPS and atrial myocytes was mediated by the secretion of IL-1β by macrophages, which inhibited the expression of atrial myocyte quaking protein (QKI) and a1C subunit of L-type calcium channel (CACNA1C) [178]. LPS reduced the effective refractory period, widened the window of vulnerability of atrial appendage cells, promoted the expression and lateral distribution of connexin 43, and activated NF-κB signaling via a1-adrenergic receptor (α1-AR) in an animal model of atrial fibrillation, indicating that chronic inflammation represented by LPS may play a role in the atrial fibrillation pathogenesis [179].

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Subjects: Cardiac & Cardiovascular Systems
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Andreea-Ioana Inceu , Maria-Adriana Neag , Anca-Elena Craciun , Anca-Dana Buzoianu
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Update Date: 22 Feb 2023
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