Cardiovascular Biomarkers: History
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Subjects: Cardiac & Cardiovascular Systems
Contributor:
Crystal Ghantous

This review summarizes some of the promising early stage protein and miRNA biomarker candidates as well as the currently used biomarkers for hypertension and other cardiovascular diseases.

  • Biomarkers
  • Hypertension
  • Inflammation
  • Cardiovascular disease

1. Introduction

1. 1. Hypertension and Vascular Smooth Muscle Cell Remodeling

VSMCs reside in the tunica media, the middle layer of blood vessels and the thickest layer in arteries. They contract and relax in response to different stimuli in order to regulate blood flow to the tissues that the vessels irrigate. In essential hypertension, small resistance arteries undergo vascular remodeling and become characterized by an increased wall thickness to lumen ratio and a narrower lumen[1][2].

Several molecular mechanisms mediate hypertension-induced vascular remodeling. The force of mechanical stretch exerted by hypertension on the vascular wall promotes the production of reactive oxygen species (ROS)[3], which in turn induce VSMC remodeling[4][5]. The excessive force of stretch mediated by hypertension also causes alterations in the extracellular matrix, activating the RhoA pathway, which in turn promotes actin cytoskeleton remodeling in VSMCs[3]; the hypertension-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (AKT) also results in vascular remodeling [6][7]. Moreover, caveolae, which are lipid raft invaginations in the plasma membrane, mediate hypertension-induced VSMC modeling via endothelial nitric oxide synthase (eNOS) and endothelin receptor type A (ETA)[8][9][10]. Studies have also shown that angiotensin II type 1 receptor (AT1), platelet-derived growth factor receptor (PDGF-R), and specific ion channels, like voltage-gated calcium channels, are implicated in hypertension-induced VSMC remodeling[6][11][12][13][14] (Figure 1).

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Figure 1. Schematic representation of vascular smooth muscle cell (VSMC) remodeling in response to hypertension. Hypertension stimulates different sensors in the plasma membrane of VSMCs, activating several signaling pathways that lead to VSMC remodeling.

1.2. Hypertension and Endothelial Dysfunction

Endothelial cells are located in the tunica intima layer of blood vessels and form the luminal surface. Blood pressure exerts two types of forces on the endothelial cells: outward mechanical stretch and shear stress. When blood pressure is low, endothelial cells secrete a number of vasoactive molecules, like angiotensin II, endothelin-1, ROS, and prostanoids, which act on VSMCs to promote VSMC contraction and subsequent vasoconstriction[15][16]. In contrast, when blood pressure rises, vasodilator substances like nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor are produced by endothelial cells[17][18].

The forces exerted by hypertension cause endothelial damage and dysfunction, resulting in reduced production of NO[19][20]. Consequently, blood pressure-induced vasodilation is compromised. Moreover, hypertension-mediated endothelial dysfunction promotes the development of atherosclerosis.

Atherosclerosis is associated with the build-up of an atheromatous plaque, which is mainly composed of oxidized low-density lipoprotein (LDL) and macrophages inside the walls of arteries. It is a risk factor for coronary artery disease, myocardial infarction (MI), hypertension, stroke, and peripheral artery disease[21][22][23][24]. Arterial calcification is associated with atheroma progression and alters the mechanical properties of the vascular wall, thereby increasing the risk of rupture of the atherosclerotic plaque[25]. Discovering distinctive biomarkers that indicate early atherosclerosis development may allow the early detection of atherosclerosis, which in turn would encourage the patient to make healthy lifestyle changes or begin treatment in order to prevent its progression.

2. Biomarkers Reflecting Hypertension Pathogenesis

Since hypertension promotes the development of other CVDs, identifying antecedent, screening, and early stage diagnostic biomarkers is crucial in preventing hypertension-associated CVDs. Biomarkers of hypertension include those that indicate oxidative stress and inflammation since hypertension is associated with these states. Interestingly, adipokines have also emerged as potential biomarkers of hypertension. The following section describes these biomarkers in detail.

2.1. Biomarkers Reflecting Oxidative Stress

Hypertension is highly associated with oxidative stress, which in turn mediates hypertension-induced cardiovascular complications[3][5]. Several molecules have been shown to reflect the oxidative state. For instance, measurements of nitrite (NO2-) and nitrate (NO3-) can be used because they are markers of NO bioavailability. NO2- and NO3- are products of oxidative degradation of NO, which physiologically causes vasodilation and prevents hypertension [26][27] (Table 4). Their increased levels indicate a reduction in NO bioavailability and are thus associated with hypertension.

Table 4. Molecules used as biomarkers of hypertension.

Molecule Function/Description Levels in Hypertension Reference(s)
Nitrate and nitrite Physiological reservoir of NO that can be reduced to NO to regulate signal transduction Elevated [27][28]
Asymmetric dimethylarginine (ADMA) Inhibits nitric oxide synthase Elevated [29]
Reactive oxygen species (ROS) Highly reactive signal transduction molecules that cause nucleic acid, lipid, and protein damage when present in high concentrations (oxidative stress) Elevated [30][31]
Uric acid Final oxidation product of purine metabolism Elevated [32][33]

Asymmetric dimethylarginine (ADMA) and uric acid are other biomarkers for hypertension (Table 4). They inhibit the production of NO[34][35], so their increased levels are associated with reduced NO bioavailability and impaired vasodilation[29][36][32]. Moreover, ADMA levels are correlated with acute coronary events and can also be used as a biomarker for adverse cardiac outcomes[37]. ROS are another indicator of hypertension, since hypertension has been shown to directly increase ROS[3][30] (Summarized in Table 4). Although the aforementioned factors are widely used for the diagnosis of hypertension, there is an increasing demand to introduce more biological markers such as proteins and genes to improve the prediction of this condition. According to the Rat Genome Database, hundreds of genes are associated with hypertension (Rat: https://rgd.mcw.edu/rgdweb/elasticResults.html?term=hypertension&chr=ALL&start=&stop=&species=Rat&category=Gene&objectSearch=true;human: https://rgd.mcw.edu/rgdweb/elasticResults.html?term=hypertension&chr=ALL&start=&stop=&species=Human&category=Gene&objectSearch=true).

2.2. Protein Biomarkers Reflecting Inflammation

Since hypertension is associated with vascular inflammation[38], markers of inflammation can be used as biomarkers for hypertension. The cell adhesion molecules vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and platelet endothelial cell adhesion molecule (PECAM) allow inflammatory cells to adhere to the vascular wall[39][40][41]. High plasma levels of these molecules have been shown to be associated with hypertension[40][41][42].

Hypertensive patients have higher circulating levels of the inflammatory cytokines IL-1β, IL-10, and tumor necrosis factor-alpha (TNF-α), indicating the potential use of these inflammatory biomarkers as markers for hypertension [43]. Elevated levels of IL-1β, IL-10, and TNF-α are also correlated with increased arterial stiffness associated with hypertension[43]. Moreover, IL-6 and TNF-α levels can be used as independent risk factors for hypertension in healthy individuals[44] (Summarized in Table 5).

Table 5. Inflammatory biomarkers of hypertension.

Inflammatory Mediators Function/Description Levels in Hypertension Reference(s)
Vascular cell adhesion molecule (VCAM) Endothelial cell surface glycoprotein that allows endothelial cell-leukocyte adhesion in inflammation Elevated [45]
Intercellular adhesion molecule (ICAM) Endothelial cell surface glycoprotein that aids in endothelial cell-leukocyte adhesion Elevated [46]
Platelet endothelial cell adhesion molecule (PECAM) Cell surface protein of platelets, monocytes, neutrophils, subsets of T cells that aids in leukocyte transendothelial migration, and a constituent of the endothelial intercellular junctions Elevated [40]
6-keto-prostaglandin F1a Stable and active metabolite of prostacyclin that promotes vasodilation and inhibits platelet aggregation Reduced [47]
C-reactive protein (CRP) Activates complement and binds to foreign and damaged cells and tissue Elevated [48]
Tumor necrosis factor (TNF-α) Pro-inflammatory cytokine involved in apoptosis, cell proliferation, differentiation, and platelet activation Elevated [44][49]
IL-10, IL-1β IL-10: Cytokine involved in mediating the inflammatory response, B cell survival, proliferation and antibody production, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity
IL-1β: Cytokine involved in regulating the inflammatory response, cell proliferation, differentiation, apoptosis, and cyclooxygenase-2 induction		 Elevated [43]
IL-6 Immune response in inflammation Elevated [44]
P-selectin Cell adhesion molecule of platelets and endothelial cells that works in the interaction of leukocytes with platelets or endothelial cells Elevated [50]
Oxidized-LDL Taken up by macrophages to form foam cells, a key step in atherosclerosis development Elevated [47]
Renin and prorenin Renin hydrolyzes angiotensinogen to angiotensin I, while prorenin is its inactive precursor Elevated [51]
Leptin - Hormone mainly produced by adipocytes that acts as a satiety factor to increase energy expenditure by signaling at the hypothalamus
- Promotes VSMC hypertrophy
- Pro-inflammatory cytokine
- Regulates puberty, menstrual cycles, and reproductive function		 Elevated [52][53]
Adiponectin - Insulin-sensitization and fatty acid oxidation
- Anti-inflammatory - Cardioprotective		 Reduced [54]

2.3. Adipokines as Biomarkers of Hypertension

We and others have shown the significant association between the hormone leptin and hypertension [3][52][53][54][55][56][57]. Leptin is an obesity-associated adipokine that physiologically reduces appetite and increases energy expenditure. Research has shown that hypertensive patients have higher circulating leptin levels[58] and that leptin can be used as a predictor of new-onset hypertension[52]. Moreover, a recent biomedical and proteomics study conducted in our lab has shown that leptin is produced by VSMCs and that its synthesis is upregulated by hypertension (unpublished data and[3]). In turn, leptin contributes to VSMC hypertrophy and promotes atherosclerosis[3][59] (Summarized in Table 5).

Adiponectin is another adipokine that is emerging as a biomarker for hypertension[60](Table 5). This anti-inflammatory protein has been shown to exert cardioprotective effects on the heart by inhibiting pressure overload-induced cardiac hypertrophy and protecting against myocardial injury after ischemia-reperfusion[61][62][63]. Studies have shown that circulating adiponectin levels are reduced in hypertensive patients[54], which may explain the detrimental effects of hypertension on the cardiovascular system. In addition, we have recently shown that adiponectin is not only expressed by adipocytes, but also VSMCs, and that adiponectin supplementation reduces hypertension-induced VSMC hypertrophy[4][64].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines8120552

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