Tetrahydrocurcumin-Related Vascular Protection: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Dimiter Avtanski.

Tetrahydrocurcumin (THC), one of the major metabolites of Curcumin (CUR), possesses several CUR-like pharmacological effects; however, its mechanisms of action are largely unknown. The effects of THC on angiogenesis in CaSki xenografted mice and the expression of vascular endothelial growth factor (VEGF) are well documented. On the other hand, as an anti-inflammatory and antioxidant compound, THC is involved in enhancing homocysteine-induced mitochondrial remodeling in brain endothelial cells. The experimental evidence regarding the mechanism of mitochondrial dysfunction during cerebral ischemic/reperfusion injury and the therapeutic potential of THC to alleviate mitochondrial cerebral dysmorphic dysfunction patterns is also scrutinized and explored. Overall, the studies on different animal models of disease suggest that THC can be used as a dietary supplement to protect against cardiovascular changes caused by various factors (such as heavy metal overload, oxidative stress, and carcinogenesis). 

  • tetrahydrocurcumin
  • vasculature
  • endothelial cells
  • mitochondria

1. Protective Effects of Tetrahydrocurcumin (THC) in Cd2+-Induced Hypertension

Sangartit et al. [33][1] reported that THC protects against Cd2+-induced hypertension, raised arterial stiffness, and vascular remodeling in mice. Furthermore, it was also discovered that the changes in mechanical forces during Cd2+ exposure may result in the adaptive remodeling of the vascular walls [34][2].
The protein production and degradation processes cause a reorganization of the extracellular matrix, which is the crucial component of hypertensive vascular remodeling [34,35][2][3]. Recent studies have provided evidence of ROS-mediated activation of matrix metalloproteinase (MMP) by the involvement of NADPH oxidase as a consequence of increased mechanical elongation [36][4]. In the study of Sangartit et al. [33][1], mice exposed to Cd2+ had higher levels of arterial MMP-2 and MMP-9 expressions, linked to higher blood pressure and changes in vascular wall composition. Other studies [37,38][5][6] have shown that Cd2+ enhanced MMP-2 and MMP-9 levels followed by the induction of inflammation and proliferation. Enhanced MMP activation and reduced arterial compliance significantly contribute to hypertensive remodeling following Cd2+ exposure [38][6].
In the recent decade, there has been an increasing interest in the function of nutritional supplements in preventing and treating hypertension. In this direction, THC, as a potent antioxidant, has been proven to be antihypertensive by causing aortic stiffness to decrease [38][6]. On the other hand, the vascular endothelial cells can generate NO, which, despite antioxidant, anti-inflammatory, and antithrombotic activities, has a wide range of bioactivities, including smooth muscle relaxation; vasodilation; and suppression of cell growth, proliferation, and migration [39][7]. Reduced NO bioavailability can be induced by the suppression of the eNOS expression [40][8], a shortage of substrate or cofactors for eNOS [41][9], accelerated NO breakdown by ROS, and a shift in the cell signaling where eNOS is not effectively activated. In general, eNOS, as mentioned above, is the primary generator of NO in the vascular system. The recent findings demonstrate a substantial decrease in the aortic eNOS expression in Cd2+-exposed mice’s aorta. This is similar to the results of Yoopan et al., who demonstrated lower eNOS levels in the blood arteries of Cd2+-induced hypertensive rats [42][10].
Cd2+-induced vascular dysfunction compromises the integrity of the vascular endothelium and increases vascular inflammation [43][11]. Furthermore, tumor necrosis factor-α (TNF-α) and other pro-inflammatory mediators can stimulate inducible NOS (iNOS) activation. This is followed by NO-mediated dysregulation as a result of increased NO production [44][12]. Through an analysis of the iNOS activity, Chauhan et al. [45][13] showed that NO derived by iNOS provoked a reduction in eNOS expression and guanylate cyclase (GC) activity, causing endothelial and smooth muscle dysfunction. Overall, the findings of Sangartit et al. [33][1] revealed that THC restores the function and structure of the vasculature in Cd2+-induced hypertensive mice via the modulation of the eNOS/iNOS regulated pathway. In addition, Cd2+ possesses the ability to generate oxidative stress by inducing ROS and reactive nitrogen species (RNS) production, depleting GSH, inhibiting sulfhydryl (SH)-dependent enzymes by replacing some essential metals required for antioxidant enzyme activity, and/or increasing cell susceptibility to oxidative attack by altering membrane integrity and fatty acid composition [46,47][14][15]. Cd2+ exposure is linked to enhanced ROS formation (particularly O2−) [48][16]. Furthermore, increased O2− production can trigger iNOS expression via increased NF-κB activity, which can enhance NO production [44][12]. As mentioned above, the induction of the iNOS results in an overabundance of NO, which interacts with O2− and generates a severely potent oxidant: peroxynitrite (ONOO−). Both O2− and ONOO− contribute to tissue damage and organ malfunction (including blood vessels, heart, liver, and kidney). THC administration lowers aortic O2− generation and the urine nitrate/nitrite ratio in a dose-dependent manner. It was also shown that reduced iNOS expression is linked to lower O2− levels and a lower nitrate/nitrite ratio, which inhibits ONOO− production and increases NO bioavailability [49][17]. In addition, heavy metals, such as Cd2+, cause many adverse effects by generating free radicals, which result in DNA damage, lipid peroxidation, and a decrease in the protein sulfhydryl (e.g., GSH) [48,50][16][18]. THC significantly suppresses oxidant production, as evidenced by the prevention of high levels of O2−, MDA, and protein carbonyls, whereas the injection of THC into mice exposed to Cd2+ enhanced endogenous antioxidant GSH [48][16]. These findings imply that vascular protection in THC-treated animals is most likely attributable to oxidative stress regulation.

2. Vascular THC Protection in Conditions of Iron Overload

In a study focusing on the role of iron sucrose in the interactions between leukocytes and endothelium, Kuo et al. [55][19] found an index for early atherogenesis and subsequent atherosclerosis in a mouse remnant kidney model. Additionally, they discovered that iron treatment of human aortic endothelial cells elevated the expression of intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and adhesion of U937 cells through upregulated NADPH oxidase and NF-κB signaling. In the same direction, [56][20] confirmed the link between inflammation and induction of iNOS, which is important for boosting NADPH oxidase activity via the c-Jun N-terminal kinase-AP1 (JNK-AP1) and Janus kinase 2/Interferon regulatory factor (Jak2/IRF) signaling pathways [57][21]. Thereby, it is proposed [58][22] that a small amount of NO generated by eNOS is required for cardiovascular homeostasis. In contrast, excessive amounts of NO produced by iNOS may harm the cardiovascular system [59][23]. Increased iNOS expression and activity have been linked to the pathophysiology of hypertension and its consequences [58][22]. The iron-induced over-regulation of iNOS causes a high NO production rate, which reacts with O2− to generate ONOO−, resulting in nitrosative stress and endothelial dysfunction [60][24]. In iron-overloaded animals, oral treatment with deferiprone (L1) together with THC causes an increase in the endothelial NO production by up-regulating eNOS expression, enhancing endothelial function, and adequate baroreflex sensitivity. L1 and THC seriously reduced NADPH oxidase expression. The inhibition of the NADPH oxidase may help improve baroreflex sensitivity in iron-overloaded conditions [61][25]. In addition to antioxidants, L1 and THC can act as chelating agents by reducing iron deposits in iron-overloaded rats. THC has been found to have high antioxidant activity via the β-diketone moiety in the neutralization of O2− and inhibiting oxidative stress [22][26]. Furthermore, THC-mediated free radical clearance may limit iNOS induction, resulting in decreased NO generation. THC can also cause iNOS reduction by inhibiting NF-κF-24]. THC restores endothelium protective properties by boosting eNOS and restoring vascular responses (61). In iron-overloaded mice, THC enhanced the antioxidant GSH and restored the redox status [61][25]. This might be related to the THC’s capacity to remove ROS mediators and boost GSH levels. Iron overload toxicity is commonly associated with free radical tissue damage. Sangartit et al. [61][25] also demonstrated that using either L1 or THC alone leads to the removal of the excess iron in the iron-overloaded condition. Furthermore, the combined therapy of L1 and THC causes non-transferrin-bound iron (NTBI) reduction in a condition of systemic iron overload (lowering blood pressure and improving baroreflex and vascular reactivity). The research of Thephinlap et al. [62][27] found that CUR and L1 therapy lowered plasma concentrations of non-transferrin-bound iron (NTBI) and malondialdehyde (MDA), and improved heart rate variability in rats with iron-induced iron overload. It has been proposed that the β-diketo moiety of CUR participated in NTBI chelation [63][28]. THC may have the same iron-chelating capabilities as CUR since it is a CUR analog with a β-diketone group that may be coupled with Fe (III) [64][29]. Although THC has a lower effect on iron chelation than L1, the synergistic effects of the two compounds in lowering iron overload could be a viable option in some severe iron overload circumstances.

3. THC-Mediated Mitochondrial Impact in Brain Vasculature

Decreased mitochondrial dynamics and malfunction play a significant role during brain ischemia. Mondal et al. [65][30] laid down fundamental knowledge about the new mechanism of mitochondrial failure during ischemia/reperfusion (I/R) injury via hyperhomocysteinemia (HHcy)-induced mitochondrial remodeling. The authors also implied that high homocysteine (Hcy) levels could indicate altered brain function during cerebral I/R. The same authors indicated that THC treatment decreased cerebral edema and cerebral blood flow and improved blood–brain barrier (BBB) damage following ischemic stroke [65][30]. BBB preservation is of utmost importance during an ischemic stroke [66][31]. THC maintains the integrity of the BBB by lowering endothelial cell damage [65][30]. Numerous studies have found total Hcy to be a significant, graded, and independent risk factor for coronary artery disease and stroke [67,68,69][32][33][34]. In addition, Mondal et al. [65][30] discovered that overall plasma and tissue Hcy levels are considerably higher in the ischemic groups compared to controls. THC treatment reduced Hcy levels in the ischemic brain. Furthermore, the same group discovered that ischemic stroke altered the expression of enzymes involved in Hcy metabolisms, such as cystathionine-β-synthase (CBS), cystathionine gamma-lyase (CSE), methylenetetrahydrofolate reductase (MTHFR), and S-adenosyl-L-homocysteine hydrolase (SAHH). When the metabolism of cysteine or methionine is disrupted, Hcy levels in the body rise. Thus, the findings of Mondal et al. [65][30] demonstrate that I/R either directly interferes with methionine metabolism or indirectly changes methionine metabolic enzymes, which results in HHcy. In general, Hcy may be transported to the mitochondria during HHcy and cause hypermethylation by raising SAHH and reducing MTHFR levels. Additionally, Hcy was linked to cerebral arteriolar stiffness, endothelial damage, and, ultimately, brain dysfunction [70][35]. In the study of Mondal et al. [65][30], the levels of mitochondrial p47phox and gp91phox were elevated in the ischemic mitochondrial fraction. In contrast, thioredoxin reductase (TR) and manganese superoxide dismutase (MnSOD) levels were lowered, summarizing that the THC treatment improved these stress markers. Additionally, because CUR is an antioxidant [71][36], it has been proven that treating animals with CUR during I/R-induced injury ameliorates mitochondrial dysfunction by reducing oxidative stress. Cellular damage caused by neurological disorders or head injuries opens a transitory breach in the mitochondrial membrane, which can significantly limit adenosine triphosphate (ATP) production and even cause ATP hydrolysis [72][37]. Damage to brain tissue caused by I/R results in decreased glucose and oxygen transport, leading to much lower ATP synthesis. Mondal et al. [65][30] detected an increase in the brain’s mitochondrial permeability transition (MPT) pore as a consequence of ischemic stroke. This was followed by a subsequent decrease in O2 intake and ATP synthesis, whereas THC therapy alleviated these alterations. The authors also discovered a significant induction of matrix metalloproteinase (MMP-9) activity in the mitochondrial fraction isolated from the ischemic brain of I/R mice. Interestingly, THC treatment can drastically reduce MMP-9 activity [65][30]. MMP-9, a member of the MMP family that generally remodels the extracellular matrix (ECM), is overexpressed following cerebral ischemia, which has been linked to rapid matrix degradation, reduced BBB integrity, and increased infarct size after stroke [65,66][30][31]. Tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2) are endogenous MMP-9 inhibitors [73][38]. The balance between MMP and TIMP is vital for correctly functioning ECM remodeling and is required for various developmental and morphogenetic processes [74][39]. In this direction, Refsum et al. [75][40] reported a considerable rise in the expression of MMP-9 and a reduction in the expression of its tissue inhibitor TIMP-2. The increased MMP-9 protein/mRNA levels destroy tight junction proteins (TJPs) and improve BBB permeability [75][40]. TJPs are critical not just for tissue integrity, but also for vascular permeability, leukocyte extravasation, and angiogenesis [76][41]. TJPs control BBB function and keep MPT pores closed, providing them with neuroprotective characteristics. Mondal et al. [75][40] found that MMP-9 activation is related to reduced expression of cellular TJPs, zonula occludens-1 (ZO1), and occludin (in both protein and mRNA levels), which leads to mitophagy. These findings reveal that mitochondrial dysfunction in the ischemic brain downregulates ZO1 and occludin, mitigated by THC treatment. These findings imply that THC modifies the ischemic impact of cerebral vascular damage, perhaps by blocking MMPs/TIMPs, limiting TJP degradation, and conserving vascular integrity. It is generally understood that the prompt clearance of damaged mitochondria by autophagy (mitophagy) is essential for cellular homeostasis and function [77][42]. According to Mondal et al. [65][30], THC inhibits mitophagy in the mouse brain following damage induced by cerebral I/R. Thus, inhibiting mitophagy with THC treatment may aid in the reduction in ischemic damage. The same group discovered that DNA methyltransferases (DNMT1 and DNMT3a), enzymes responsible for DNA methylation and gene expression were drastically elevated in ischemic mitochondria. To further examine the mechanisms of THC-induced normalization of DNMT in ischemic mitochondria, Mondal et al. [65][30] found that the recovery DNMT levels were close to those of the control group. Furthermore, the S-Adenosylmethionine/S-Adenosylhomocysteine (SAM/SAH) ratio as a biomarker for clinical diagnosis of the atherosclerosis is much higher in the ischemic brain. More specifically, MMP-9 activity is elevated in ischemic mitochondria, resulting in a reduction in TIMP-2 regulation. TIMP-2 protein expression is considerably decreased in ischemia due to increased DNA hypermethylation and epigenetic inhibition of gene transcription [65][30]. Treatment with 5-Aza drastically changed TIMP-2 synthesis in the ischemic condition. These findings reveal that epigenetic DNA hypermethylation is triggered after ischemia reperfusion-induced damage, resulting in TIMP-2 suppression and ECM remodeling. The latter is one of the fundamental mechanisms that must be considered when investigating the THC-associated mechanisms related to ischemic conditions).

4. THC-Induced Mitochondrial Remodeling in Brain Vascular Endothelial Cells

Many neurodegenerative disorders, including ischemic stroke and Alzheimer’s disease, are associated with mitochondrial dysfunction [78,79,80][43][44][45]. As discussed above, some disorders have been linked to Hcy [81,82][46][47]. For these reasons, Vacek et al. [83][48] investigated the influence of THC on the control of mitochondrial dynamics in brain endothelial cells during HHcy. More specifically, they investigated how increased Hcy levels dysregulate mitochondrial fission and fusion equilibrium in mouse brain endothelial cells. Taking that endothelium regulates nutrition transport, it is reasonable to predict that damaged endothelium in the brain could substantially contribute to the pathophysiology of neurodegenerative disorders. According to Marchi et al. [80][45], detrimental stress for these cells is most typically associated with the increased generation of mitochondrial ROS. Furthermore, Vacek et al. [83][48] discovered a considerable increase in ROS production in Hcy-treated brain endothelial cells. THC therapy later showed a protective effect in Hcy-treated brain endothelial cells based on its free radical scavenging capability. Autophagy is frequently addressed in such research as a control process that balances the involved systems. Autophagy is a type of programmed cell death that is not apoptotic. Most evidence suggests that autophagy is primarily a pro-survival rather than a pro-death mechanism, at least in cells with intact apoptotic machinery [84][49]. Mitophagy, or selective mitochondrial autophagy, is a critical mitochondrial quality control process that relies on the presence of particular mitophagy regulators that guarantee selective mitochondrial sequestration [84][49]. In their study, Vacek et al. [83][48] found an Hcy-induced increase in the autophagy marker microtubule-associated protein light chain 3 (LC3) and a significant increase in its receptor expression, normalized by THC treatment.
Hollenbeck and Saxton [44][12] reported that the fusion and fission of these dynamic organelles are required for mitochondrial function. Proteins that control mitochondrial dynamics are linked to various cellular processes [85][50]. Mitochondrial fission and fusion are frequently viewed as a finely calibrated equilibrium in cells. However, they are not fully integrated, and quantitative knowledge of how these processes interact with other mitochondrial cellular processes is lacking. Mitochondrial fission and fusion play roles in mitochondrial integrity, electrical and biochemical binding, turnover, and DNA segregation and protection. Vacek et al. [83][48] concluded that higher fission events lead to more mitophagy events. THC, on the other hand, significantly inhibited such effects in the cells. Furthermore, fission and fusion machinery have been linked to programmed cell death pathways [86][51]. The previous restudyearch also revealed that Hcy induces endothelial cell death [86][51]. Vacek et al. [83][48] also discovered that Hcy significantly increased cell apoptosis, which was inhibited by THC administration. This can be linked to lower levels of total intracellular ROS, lending credence to the theory that mitophagy is caused by oxidative stress in the cell. Hence, it should be highlighted that THC is engaged in controlling mitochondrial fusion, and preliminary research in the field indicates that it has a favorable influence. An in-depth study is required to provide a better understanding of THC participation in the control of such systems.

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