**1. Introduction**

Cardiovascular diseases consider as one of the major causes of death, contributing to approximately 30% of all deaths globally. In Kingdom of Saudi Arabia, approximately 37% deaths are caused by cardiovascular diseases [1]. Elevated cardiovascular diseaserelated morbidity and mortality result from a complex pathophysiological process including activation of many signaling transduction pathways, resulting in modification in cardiac/vascular structure, remodeling, and ultimately alteration in the functionality, which contributes to disease progression. Of importance, G protein-coupled receptors (GPCR) play a key fundamental role in various transductions signaling that participate in cardiovascular diseases pathophysiological progression. GPCRs are a

superfamily of heptahelical integral membrane proteins, which respond to various stimuli. They are responsible for transduction of a plethora of signaling networks that involve in physiological and pathological actions in cardiovascular system [2, 3]. The activation of α-adrenergic, β-adrenergic, muscarinic, angiotensin II type 1 receptor (AT1) and endothelin (ETA) receptors are involved in cardiac contractility, vascular resistance, vascular and cardiac remodeling. In addition, the effect of neurohumoral systems on cardiac contractility and blood vessel tone mainly transmit their signals via corresponding GPCR. These types of receptors and their downstream transduction systems are targets of various drugs used in the treatment of cardiovascular diseases [4].

In case of hypertension, GPCRs play fundamental function in blood vessel diameter, which is mainly controlled by either contraction or relaxation of vascular smooth muscle cells. During contraction, GPCR mediated phosphorylation of contractile proteins [5]. Vasoactive peptides such as noradrenaline, angiotensin II, endothelin 1, and vasopressin activated their corresponding Gαq coupled GPCR, results in stimulation of phospholipase C-β, resulting in the formation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to their corresponding receptors which is inositol trisphosphate receptors (IP3Rs) in the sarcoplasmic reticulum; the intracellular Ca2+ store. Activation of IP3Rs resulting in efflux of Ca2+ into the cytoplasm. On other hand, DAG activates protein kinase C (PKC), promoting Ca2+ influx via enhancing the vascular channels activity such as voltage-dependent L-type Ca2+ channels. Elevated intracellular Ca2+ concentration [Ca2+]i binds to calmodulin, creating Ca2+-calmodulin complex which activate MLC kinase (MLCK) followed by phosphorylation of contractile proteins that promote myosin-actin filament interactions and consequently smooth muscle contraction [6–11]. Contraction of vascular smooth muscle cells could persist via regulation of MLC phosphatase (MLCP). Vasoactive peptides also regulate the dephosphorylation of MLC phosphatase via different mechanisms. They utilize the PLC-DAG-PKC pathway, which in turn inhibits phosphatase activity and thus stimulates persistent contraction [12]. In addition, they activate RhoA-Rho kinase pathway, which phosphorylates MLCP and inhibits its activity [13, 14]. On the other hand, a low [Ca2+]i concentration and increased activity of MLC phosphatase promoting vascular smooth muscle cell relaxation [15]. Gαs-coupled GPCR mediated blood vessel relaxation. Adrenaline, as vasodilator, acts on corresponding receptors, recruiting Gαs to stimulate adenylyl cyclase (AC), leading to the formation of cAMP and then activation of protein kinase A (PKA). PKA plays important role in decreasing [Ca2+]i concentrations via phosphorylation of MLCK. This results in activation of calcium pumps in the plasma membrane and sarcoplasmic reticulum. Furthermore, promotes cell hyperpolarization by opening K<sup>+</sup> channels promoting relaxation of vascular smooth muscle cells [8, 16, 17].

In case of heart failure, GPCR such as β-adrenergic receptors plays an essential role in cardiac function and in cardiac myocytes contractility. β1-adrenergic receptors couple to Gαs that activates adenylate cyclase (AC) and enhances cAMP mediate protein kinase A (PKA) activation which regulates different intracellular, sarcolemma, and myofibrillar substrates, mediating positive inotropic and chronotropic effects [18]. Gβγ subunits also activate downstream effectors that participate in cardiac transduction pathways. Moreover, it has been reported that overexpression of β1-adrenergic receptors triggers early myocytes hypertrophy and interstitial fibrosis followed by marked cardiac dysfunction in mice [18]. In addition, β1-adrenergic receptors activate various downstream signaling participating in cardiac pathophysiological processes such as cardiac hypertrophy, which might progress to heart failure development [19–21]. β2-adrenergic receptors can couple to a dual Gαs/Gαi subunits, it

### *DOI: http://dx.doi.org/10.5772/intechopen.105403 G Protein-Coupled Receptor Regulation in Cardiovascular Disease: Role of G Protein-Coupled…*

has been implicated in differential β2-adrenergic receptors mediated signaling such as in myocyte apoptosis [22]. Therefore, β-adrenoceptor blockers are one of the standard pharmacotherapeutics agents used in the treatment of heart failure patients [23]. β-blockers also have been shown to reduce disease progression, mortality, and morbidity in patients with heart failure with reduced ejection fraction (HFrEF) [24]. This effect appears primarily related to the ability of β-adrenoceptor blockers to protect the heart from the harmful effects of receptor over-stimulation [25].

As the effect of neurohumoral systems on cardiovascular system mainly transmits their signals via GPCRs, understanding of the GPCR regulation and their G-protein dependent/independent signaling reveals a novel therapeutic approach that could attenuate cardiovascular-related complications. In current chapter, we provide insight into the potential effect of GPCR negative regulators, focusing particularly on G protein-coupled receptor kinases (GRKs) and their possible effect on cardiovascular diseases.
