Abstract
Pulmonary arterial hypertension (PAH) is a clinical condition characterized by pulmonary arterial remodeling and vasoconstriction, which promote chronic vessel obstruction and elevation of pulmonary vascular resistance. Long-term right ventricular (RV) overload leads to RV dysfunction and failure, which are the main determinants of life expectancy in PAH subjects. Therapeutic options for PAH remain limited, despite the introduction of prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylyl cyclase stimulators within the last 15 years. Through addressing the pulmonary endothelial and smooth muscle cell dysfunctions associated with PAH, these interventions delay disease progression but do not offer a cure. Emerging approaches to improve treatment efficacy have focused on beneficial actions to both the pulmonary vasculature and myocardium, and several new targets have been investigated and validated in experimental PAH models. Herein, we review the effects of adenosine and adenosine receptors (A1, A2A, A2B, and A3) on the cardiovascular system, focusing on the A2A receptor as a pharmacological target. This receptor induces pulmonary vascular and heart protection in experimental models, specifically models of PAH. Targeting the A2A receptor could potentially serve as a novel and efficient approach for treating PAH and concomitant RV failure. A2A receptor activation induces pulmonary endothelial nitric oxide synthesis, smooth muscle cell hyperpolarization, and vasodilation, with important antiproliferative activities through the inhibition of collagen deposition and vessel wall remodeling in the pulmonary arterioles. The pleiotropic potential of A2A receptor activation is highlighted by its additional expression in the heart tissue, where it participates in the regulation of intracellular calcium handling and maintenance of heart chamber structure and function. In this way, the activation of A2A receptor could prevent the production of a hypertrophic and dysfunctional phenotype in animal models of cardiovascular diseases.
Highlights
Pulmonary hypertension (PH) refers to a complex group of cardiopulmonary diseases that may lead to right-sided heart failure and reduced life expectancy (Galie et al, 2016)
That contributes to muscularization of the distal vessels (Sartore et al, 2001; Sisbarro et al, 2005; Sakao et al, 2009). These findings indicate that any effect on bone morphogenetic protein receptor-2 (BMPR2) signaling may trigger abnormal communication between endothelial cells (ECs), pulmonary arterial smooth muscle cells (PASMCs), and fibroblasts via growth factors
The spontaneous Pulmonary arterial hypertension (PAH) and altered pulmonary arteries (PAs) remodeling were supported by the anatomical localization of A2A in the vasculature, further demonstrating the functional activation of A2A in ECs. These findings suggest that the effect of adenosine in PAH is likely mediated by the A2A receptor in pulmonary vessels (Xu et al, 2011)
Summary
Pulmonary hypertension (PH) refers to a complex group of cardiopulmonary diseases that may lead to right-sided heart failure and reduced life expectancy (Galie et al, 2016). The poor prognosis of PAH is mainly a consequence of long-term pressure overload in the RV chamber, which initially responds with adaptive myocardial hypertrophy. This response is followed by progressive contractile dysfunction, global heart failure, and premature death (Voelkel et al, 2006; Sztrymf et al, 2010). The work focuses on AR activities in the small circulation, in PAH pathogenesis, including the aberrant cellular proliferation and influx of inflammatory cells in and around various components of the vascular wall, as well as the distinct roles of ARs in RV cells. The main goal of this review is to answer an intriguing question: Does a specific AR exist that could be considered as a future target with pleiotropic potential in the whole cardiopulmonary system of patients with PAH?
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