The Role of G Protein-Coupled Receptors in the Right Ventricle in Pulmonary Hypertension

Abstract

Pressure overload of the right ventricle (RV) in pulmonary arterial hypertension (PAH) leads to RV remodeling and failure, an important determinant of outcome in patients with PAH. Several G protein-coupled receptors (GPCRs) are differentially regulated in the RV myocardium, contributing to the pathogenesis of RV adverse remodeling and dysfunction. Many pharmacological agents that target GPCRs have been demonstrated to result in beneficial effects on left ventricular (LV) failure, such as beta-adrenergic receptor and angiotensin receptor antagonists. However, the role of such drugs on RV remodeling and performance is not known at this time. Moreover, many of these same receptors are also expressed in the pulmonary vasculature, which could result in complex effects in PAH. This manuscript reviews the role of GPCRs in the RV remodeling and dysfunction and discusses activating and blocking GPCR signaling to potentially attenuate remodeling while promoting improvements of RV function in PAH.

Keywords: G protein-coupled receptor; dysfunction; pulmonary hypertension; remodeling; right ventricle.

Figure 1

Endothelin signaling pathways. ET_AR, ET_BR, endothelin receptors; ET-1, endothelin; IP₃, inositol 1,4,5-trisphosphate; Ca²⁺, Calcium; NFAT4, nuclear factor of activated T cells 4; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; p-AKT, phospho-Protein kinase B; p-ERK, phospho- extracellular signal-regulated kinases; Gαi, Gαq, G-proteins.

Figure 2

Adrenergic receptors signaling pathways. CaMK II, Ca²⁺/Calmodulin-Dependent Protein Kinase II; GRK2, beta-adrenergic receptor kinase 1; AC, Adenylyl cyclase; cAMP, Cyclic adenosine monophosphate; PKA, protein kinase A; Ca²⁺, Calcium; nNOS, neuronal nitric oxide synthases; MAPK, mitogen-activated protein kinase; P13K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; Gαs, Gαi, Gβγ, G-proteins.

Figure 3

Prostanoid receptors signaling pathways. PGE₂, Prostaglandin E2; PGF₂, Prostaglandin F2; PGI₂, Prostaglandin I2 (Prostacyclin); EP, Prostaglandin receptors; FP, Prostanoid receptors; IP, Prostacyclin receptor; PLC β, 1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-1; ERK, extracellular signal-regulated kinases IP3, inositol 1,4,5-trisphosphate; Ca²⁺, Calcium; MAPK, mitogen-activated protein kinase; Gαs, Gαi, Gαq, G-proteins.

Figure 4

Angiotensin mediated signaling pathways. Ang, angiotensin; ACE, Angiotensin-converting enzyme; AT₁R, Angiotensin II receptor type 1; AT₂R, Angiotensin II receptor type 2; Mas1, Proto-oncogene Mas; PRCP, Lysosomal Pro-X carboxypeptidase; Gαi, Gαq, G-proteins.