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.
Highlights
Right ventricular (RV) dysfunction and failure predict mortality in a number of cardiopulmonary diseases including pulmonary arterial hypertension (PAH) [1], heart failure [2,3,4] and chronic obstructive pulmonary disease (COPD) [5, 6]
The right ventricle (RV) undergoes favorable remodeling characterized by an increase in RV wall thickness, dilation and mass mediated by cardiomyocyte hypertrophy and moderate extracellular matrix deposition to maintain its contractility to the increased afterload [7, 8]
A number of G protein-coupled receptors (GPCRs) are differentially regulated in the RV myocardium in response to pressure overload in both PAH patients and preclinical models of RV remodeling (Table 1)
Summary
Right ventricular (RV) dysfunction and failure predict mortality in a number of cardiopulmonary diseases including pulmonary arterial hypertension (PAH) [1], heart failure [2,3,4] and chronic obstructive pulmonary disease (COPD) [5, 6]. A direct comparison of the dual ET receptor antagonist bosentan and the ETA-selective antagonist ambrisentan in the MCT model demonstrated that, compared to bosentan, ambrisentan significantly increased prostacyclin synthase I expression [97] Both antagonists reduced RV systolic pressure, pulmonary vascular remodeling, and RV hypertrophy. In the Dahl-salt rat model of systemic hypertension, macitentan administered in addition to the maximally effective dose of bosentan further reduced mean arterial pressure (MAP) [97] These differences between ERAs is likely a combination of their different patterns of ETA/BR selectivity and different potencies, but some of it may be due to their selective inhibition of different signaling pathways downstream of these receptors.
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