Cardiovascular Biology

The hypertrophic growth of the heart occurs in response to hemodynamic stress (blood pressure-related and blood flow‒related shear stress) to support cardiac performance and reduce ventricular wall tension and oxygen consumption. Physical activity or pregnancy can cause mild and reversible heart growth, known as physiological hypertrophy. On the flip side, pathological hypertrophy may occur due to chronic stressors, including hypertension. Pathological hypertrophy is associated with excessive enlargement of the ventricles, myocardial dysfunction and fibrosis and heart failure (5).

Signaling pathways involved in cardiac hypertrophy include MAPK, Akt, calcineurin/NFAT and CaMKII/MEF2 signaling pathways (6, 7). For example, calcineurin is activated when there’s a chronic increase in intracellular calcium levels, enabling it to bind to NFAT. This activation leads to the translocation of NFAT into the nucleus, where it works with other transcription factors, such as MEF2 or GATA1, to activate genes associated with hypertrophy (8, 9).

Endothelin-1 (ET-1) is a potent vasoactive peptide produced primarily by endothelial cells that line the blood vessels. It regulates vascular tone and blood pressure by binding to two types of G-protein-coupled receptors, ETA and ETB, on the surface of vascular smooth muscle cells and endothelial cells. This binding initiates a cascade of intracellular signaling events that lead to vasoconstriction, increased cellular proliferation and inflammation. (13)

In ET-1 signaling, the binding of ET-1 to the ETA receptor on vascular smooth muscle cells activates phospholipase C, producing inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 triggers calcium release from the sarcoplasmic reticulum, while DAG activates protein kinase C (PKC), resulting in muscle contraction and vasoconstriction. Binding to the ETB receptor on endothelial cells can release nitric oxide (NO) and prostacyclin, which are vasodilators and serve as a counter-regulatory mechanism to balance the vasoconstrictive effects of ET-1. (14)

ET-1 signaling is significant in cardiovascular diseases such as hypertension, atherosclerosis and heart failure. Overproduction of ET-1 leads to sustained vasoconstriction and increased vascular resistance in hypertension, while in atherosclerosis, it promotes vascular smooth muscle cell proliferation, inflammation and fibrosis, contributing to plaque formation. In heart failure, elevated ET-1 levels exacerbate cardiac dysfunction by increasing afterload and promoting myocardial fibrosis, making ET-1 signaling a key therapeutic target for these conditions. (14, 15)

Although ET-1 is significantly involved in many cardiovascular diseases, only a few ET-1-targeted treatments exist. One is the ET receptor antagonist, approved for treating pulmonary arterial hypertension. (14)

Nitric oxide signaling primarily functions in a paracrine manner and plays a crucial role in regulating cardiovascular functions and homeostasis, particularly in vascular control (19). eNOS (endothelial nitric oxide synthase), the enzyme responsible for generating nitric oxide in endothelial cells, is involved in vasodilating blood vessels, vascular remodeling, vascular protection against thrombosis and atherosclerosis and protection against endothelial dysfunction (19, 20).

Aberrant NO signaling, particularly dysfunctional eNOS, is implicated in pathological states in cardiovascular diseases, including endothelial dysfunction, atherosclerosis, arterial hypertension, cardiac hypertrophy and heart failure, making it a promising therapeutic target for treating these pathologies (20).

Apelin is a hormone peptide in cardiovascular, pulmonary and other tissues. The apelin receptor (APJ) is a 7-transmembrane G-protein-coupled receptor found in various cell types, including cardiomyocytes and endothelial cells. The apelin/apelin receptor system is activated when the APJ receptor binds to apelin and regulates cell proliferation, apoptosis, inflammation and revascularization (1, 2).

The apelin signaling pathway promotes physiological processes involved in cardiovascular development, function and homeostasis, including myocardial contractility, angiogenesis, fluid homeostasis, energy expenditure, glucose homeostasis, vascular function, endothelial function and blood pressure (3, 4). The binding of apelin to APJ activates downstream effectors like phosphatidylinositol-3 kinase (PI3K), Akt and extracellular signal-regulated kinases (ERK), which play crucial roles in these processes. For instance, the activation of PI3K/Akt signaling is critical for cell survival and growth, while ERK signaling contributes to cell proliferation and differentiation.

Dysregulated apelin signaling is implicated in many cardiovascular diseases, including atherosclerosis, coronary artery disease, hypertension and heart failure, highlighting its potential as a therapeutic target.

β-Adrenergic receptors (β-ARs) are G protein-coupled receptors that activate adenylyl cyclase (AC), which produces cyclic AMP (CAMP) to activate responses relevant to cardiac function and injury (10, 11). There are three subtypes of β-ARs, β1, β2 and β3, with β1 being the primary subtype expressed in the heart. β-adrenergic signaling regulates cardiovascular-related functions, including heart rate, myocardial contractility, cardiac remodeling and cardiac output (12).

β-ARs signaling dysfunction is associated with pathological events involved in heart failure and the aging heart. β-ARs can be deactivated due to excessive G protein-coupled receptor kinases (GRKs) activity. Regular GRK activity supports cardiovascular homeostasis. However, increased levels of GRKs like GRK2 can lead to dysfunctional β-AR signaling. It has been shown that heightened GRK2 expression and activity results in the reduction of β1AR- and β2AR-mediated cardiac reserve function. This, in turn, can lead to inappropriate cardiac remodeling and heart failure (10).

In response to hypoxia stress, cells activate a series of downstream pathways, including the hypoxia signaling pathway, principally regulated by the hypoxia-inducible factor (HIF). HIF regulates genes involved in inflammation, vascular remodeling and angiogenesis, enabling the organism to respond and adjust to a low-oxygen environment (16, 17).

Hypoxia signaling significantly contributes to the cardiovascular system in health and diseases. During embryonic heart development, gestational hypoxia triggers specific pathways essential for the development of heart chambers and septum. In the adult heart, hypoxia happens periodically as a physiological response to high altitudes and exercise, for instance, to enable the body to adapt to changes in oxygen availability. It is also involved in pathological events, including cardiomyocyte hypertrophy, inflammation, ischemia and fibrosis (18).

Unsurprisingly, hypoxia signaling is significantly implicated in cardiovascular diseases. HIF-1α, for instance, is widely expressed in cardiovascular diseases as an indicator of atherosclerosis, pulmonary arterial hypertension (PAH), cardiac hypertrophy, cardiomyopathy, arrhythmias, congenital heart diseases, heart failure and other cardiovascular diseases (18). HIF-1α contributes to pathological events implicated in these cardiovascular diseases, including endothelial dysfunction, smooth muscle proliferation, inflammation and angiogenesis through the activation of genes such as vascular endothelial growth factor (VEGF), erythropoietin (EPO) and CXCL1 (17).

Therapeutic approaches targeting HIF show promising potential in treating these cardiovascular diseases.