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

Viswanathan, Gayathri; Mamazhakypov, Argen; Schermuly, Ralph T.; Rajagopal, Sudarshan

doi:10.3389/fcvm.2018.00179

Cited by 15 publications

(18 citation statements)

References 222 publications

(224 reference statements)

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“…The focus of this review is on the molecular mechanisms that may contribute to maladaptive remodeling in the RV. Although many pathways are currently under study in the pathogenesis of RV failure (13)(14)(15), this review will specifically focus on select molecular events and pathways that are supported by strong pre-clinical and human (clinical) data that have resulted in, or will lead to, clinical trials in PAH patients.…”

Section: Review Article On Right Ventricular Dysfunctionmentioning

confidence: 99%

Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism

Agrawal¹,

Lahm²,

Hansmann³

et al. 2020

Cardiovasc Diagn Ther

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Pulmonary arterial hypertension (PAH) is a rare, life-threatening condition characterized by dysregulated metabolism, pulmonary vascular remodeling, and loss of pulmonary vascular cross-sectional area due to a variety of etiologies. Right ventricular (RV) dysfunction in PAH is a critical mediator of both long-term morbidity and mortality. While combinatory oral pharmacotherapy and/or intravenous prostacyclin aimed at decreasing pulmonary vascular resistance (PVR) have improved clinical outcomes, there are currently no treatments that directly address RV failure in PAH. This is, in part, due to the incomplete understanding of the pathogenesis of RV dysfunction in PAH. The purpose of this review is to discuss the current understanding of key molecular mechanisms that cause, contribute and/or sustain RV dysfunction, with a special focus on pathways that either have led to or have the potential to lead to clinical therapeutic intervention. Specifically, this review discusses the mechanisms by which vessel loss and dysfunctional angiogenesis, sex hormones, and metabolic derangements in PAH directly contribute to RV dysfunction. Finally, this review discusses limitations and future areas of investigation that may lead to novel understanding and therapeutic interventions for RV dysfunction in PAH.

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Section: Review Article On Right Ventricular Dysfunctionmentioning

confidence: 99%

Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism

Agrawal¹,

Lahm²,

Hansmann³

et al. 2020

Cardiovasc Diagn Ther

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“… 9 However, the roles of ET-1 and its receptors in the pathogenesis of RV remodeling are poorly understood. 11 Macitentan is a dual ERA developed by modifying the chemical structure of bosentan to increase safety and efficacy, 12 which displays sustained receptor binding capacity and better tissue penetration. 13 The phase III clinical trial SERAPHIN showed that macitentan reduces morbidity and mortality, with improving pulmonary hemodynamics and 6-min walk distance (6MWD).…”

Section: Introductionmentioning

confidence: 99%

Effects of macitentan and tadalafil monotherapy or their combination on the right ventricle and plasma metabolites in pulmonary hypertensive rats

et al. 2020

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“…Furthermore, the mTORC1 is upregulated in right ventricle (RV) myocardium from rats with severe experimental PH and contributes to cardiomyocyte hypertrophy (16). Although prostanoid receptors and PKA play important roles in RV remodeling (17), the role of DP1 in the right heart is not well studied, and a potential link between DP1 and mTORC1 in the hypertrophic RV response to PAH remains to be determined.…”

mentioning

confidence: 99%

mTORC1 in Pulmonary Arterial Hypertension. At the Crossroads between Vasoconstriction and Vascular Remodeling?

Goncharova

Simon

Yuan

2020

Am J Respir Crit Care Med

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Pulmonary arterial hypertension (PAH) is a progressive and fatal disease with no cure. Pulmonary arterial pressure (PAP) is a function of cardiac output and pulmonary vascular resistance (PVR). In patients with PAH, the increased PAP is mainly due to increased PVR. The major causes for the elevated PVR and PAP are sustained pulmonary vasoconstriction, concentric pulmonary vascular remodeling, in situ thrombosis, and increased pulmonary vascular wall stiffness. Current therapies, however, target mainly vasoconstriction, and despite the advent of 14 medical therapies across three vasodilation pathways (prostacyclin, nitric oxide, and endothelin-1), the disease remains severe and life threatening. Pulmonary vascular remodeling is caused, at least in part, by increased proliferation and/or survival of resident pulmonary vascular cells, and antiproliferative/proapoptotic strategies are now under development as disease-modifying therapies for PAH. Yet the mechanisms for vasoconstriction (and/or vasodilation) and vascular remodeling are not entirely separate. Drugs that are effective for treatment of PAH may attenuate pulmonary vasoconstriction and also inhibit pulmonary vascular remodeling. One of the therapeutic examples is prostacyclin or its chemically stable analog, treprostinil, a potent vasodilator that is currently in use for the treatment of PAH. It has been noted that, in addition to its vasodilatory effect, prostacyclin or treprostinil, when given in high doses, attenuates experimental pulmonary hypertension (PH) by inhibiting proliferation of pulmonary artery smooth muscle cells (PASMCs). Interestingly, in addition to canonical activation of the EP 2 (prostaglandin E2 receptor 2) and the PPAR-g (peroxisome proliferator-activated receptor-g), prostacyclin inhibits cell proliferation induced by PDGF (platelet-derived growth factor) and transforming growth factor b, suggestive of EP 2-independent mechanisms of action (1-3). In this issue of the Journal, He and colleagues (pp. 1263-1276) uncover another enticing link between the vasodilatory prostacyclin axis and antiproliferative signaling in the pulmonary vasculature (4). The authors demonstrate that DP1 (D prostanoid receptor subtype 1), for which treprostinil acts as an agonist, is downregulated in PASMCs from patients with PAH and animals with experimental PH. Intriguingly, DP1 deficiency exacerbated pulmonary artery (PA) remodeling in mice with hypoxia-induced PH via activation of the mTOR (mechanistic target of rapamycin) complex 1 (mTORC1) (Figure 1). The mTOR, a fundamental regulator of cellular homeostasis, acts through two functionally This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.

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

Cited by 15 publications

References 222 publications

Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism

Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism

Effects of macitentan and tadalafil monotherapy or their combination on the right ventricle and plasma metabolites in pulmonary hypertensive rats

mTORC1 in Pulmonary Arterial Hypertension. At the Crossroads between Vasoconstriction and Vascular Remodeling?

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