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

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

Clinical and Molecular Implications of Osteopontin in Heart Failure

The matricellular protein osteopontin modulates cell–matrix interactions during tissue injury and healing. A complex multidomain structure of osteopontin enables it not only to bind diverse cell receptors but also to interact with various partners, including other extracellular matrix proteins, cytokines, and growth factors. Numerous studies have implicated osteopontin in the development and progression of myocardial remodeling in diverse cardiac diseases. Osteopontin influences myocardial remodeling by regulating extracellular matrix production, the activity of matrix metalloproteinases and various growth factors, inflammatory cell recruitment, myofibroblast differentiation, cardiomyocyte apoptosis, and myocardial vascularization. The exploitation of osteopontin loss- and gain-of-function approaches in rodent models provided an opportunity for assessment of the cell- and disease-specific contribution of osteopontin to myocardial remodeling. In this review, we summarize the recent knowledge on osteopontin regulation and its impact on various cardiac diseases, as well as delineate complex disease- and cell-specific roles of osteopontin in cardiac pathologies. We also discuss the current progress of therapeutics targeting osteopontin that may facilitate the development of a novel strategy for heart failure treatment

Novel Therapeutic Targets for the Treatment of Right Ventricular Remodeling: Insights from the Pulmonary Artery Banding Model

Right ventricular (RV) function is the main determinant of the outcome of patients with pulmonary hypertension (PH). RV dysfunction develops gradually and worsens progressively over the course of PH, resulting in RV failure and premature death. Currently, approved therapies for the treatment of left ventricular failure are not established for the RV. Furthermore, the direct effects of specific vasoactive drugs for treatment of pulmonary arterial hypertension (PAH, Group 1 of PH) on RV are not fully investigated. Pulmonary artery banding (PAB) allows to study the pathogenesis of RV failure solely, thereby testing potential therapies independently of pulmonary vascular changes. This review aims to discuss recent studies of the mechanisms of RV remodeling and RV-directed therapies based on the PAB model

Mast Cells in Cardiac Remodeling: Focus on the Right Ventricle

In response to various stressors, cardiac chambers undergo structural remodeling. Long-term exposure of the right ventricle (RV) to pressure or volume overload leads to its maladaptive remodeling, associated with RV failure and increased mortality. While left ventricular adverse remodeling is well understood and therapeutic options are available or emerging, RV remodeling remains underexplored, and no specific therapies are currently available. Accumulating evidence implicates the role of mast cells in RV remodeling. Mast cells produce and release numerous inflammatory mediators, growth factors and proteases that can adversely affect cardiac cells, thus contributing to cardiac remodeling. Recent experimental findings suggest that mast cells might represent a potential therapeutic target. This review examines the role of mast cells in cardiac remodeling, with a specific focus on RV remodeling, and explores the potential efficacy of therapeutic interventions targeting mast cells to mitigate adverse RV remodeling

Clinical and Molecular Implications of Osteopontin in Heart Failure

The matricellular protein osteopontin modulates cell–matrix interactions during tissue injury and healing. A complex multidomain structure of osteopontin enables it not only to bind diverse cell receptors but also to interact with various partners, including other extracellular matrix proteins, cytokines, and growth factors. Numerous studies have implicated osteopontin in the development and progression of myocardial remodeling in diverse cardiac diseases. Osteopontin influences myocardial remodeling by regulating extracellular matrix production, the activity of matrix metalloproteinases and various growth factors, inflammatory cell recruitment, myofibroblast differentiation, cardiomyocyte apoptosis, and myocardial vascularization. The exploitation of osteopontin loss- and gain-of-function approaches in rodent models provided an opportunity for assessment of the cell- and disease-specific contribution of osteopontin to myocardial remodeling. In this review, we summarize the recent knowledge on osteopontin regulation and its impact on various cardiac diseases, as well as delineate complex disease- and cell-specific roles of osteopontin in cardiac pathologies. We also discuss the current progress of therapeutics targeting osteopontin that may facilitate the development of a novel strategy for heart failure treatment

Right Ventricular Remodeling and Dysfunction in Obstructive Sleep Apnea: A Systematic Review of the Literature and Meta-Analysis

Background. Recent studies have reported that obstructive sleep apnea (OSA) patients present alterations in right ventricular (RV) structure and function. However, large randomized controlled trials evaluating the impact of OSA on the right ventricle are lacking. Methods. A comprehensive electronic database (PubMed, Web of Science, and Google Scholar) and reference search up to October 30, 2016, was performed. A systematic review and meta-analysis were performed to assess RV structure and function in OSA patients based on conventional echocardiography and tissue Doppler imaging. Results. Twenty-five studies with 1,503 OSA patients and 796 controls were included in this study. OSA patients exhibited an increase in RV internal diameter (weighted mean difference (WMD) (95% confidence intervals (CIs)) 2.49 (1.62 to 3.37); p=0.000) and RV wall thickness (WMD (95% CIs) 0.82 (0.51 to 1.13); p=0.000). Furthermore, OSA patients had a significantly elevated RV myocardial performance index (WMD (95% CI) 0.08 (0.06 to 0.10); p=0.000), decreased RV S’ (WMD (95% CI) −0.95 (−1.59 to −0.32); p=0.003), tricuspid annular plane systolic excursion (WMD (95% CI) −1.76 (−2.73 to −0.78); p=0.000), and RV fractional area change (WMD (95% CI) −3.16 (−5.60 to −0.73); p=0.011). Conclusion. OSA patients display RV dilatation, increased wall thickening, and altered RV function

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers

Adverse right ventricular (RV) remodeling leads to ventricular dysfunction and failure that represents an important determinant of outcome in patients with pulmonary hypertension (PH). Recent evidence indicates that inflammatory activation contributes to the pathogenesis of adverse RV remodeling and dysfunction. It has been shown that accumulation of inflammatory cells such as macrophages and mast cells in the right ventricle is associated with maladaptive RV remodeling. In addition, inhibition of inflammation in animal models of RV failure ameliorated RV structural and functional impairment. Furthermore, a number of circulating inflammatory mediators have been demonstrated to be associated with RV performance. This work reviews the role of inflammation in RV remodeling and dysfunction and discusses anti-inflammatory strategies that may attenuate adverse structural alterations while promoting improvement of RV function

Yarsagumba is a Promising Therapeutic Option for Treatment of Pulmonary Hypertension due to the Potent Anti-Proliferative and Vasorelaxant Properties

Background and objectives: Pulmonary hypertension (PH) is characterized by the vasoconstriction and abnormally proliferative vascular cells. The available allopathic treatment options for PH are still not able to cure the disease. Alternative medicine is becoming popular and drawing the attention of the general public and scientific communities. The entomogenous fungus Yarsagumba (Cordyceps sinensis) and its biologically active ingredient cordycepin may represent the therapeutic option for this incurable disease, owing to their anti-inflammatory, vasodilatory and anti-oxidative effects. Methods: In this study, we investigated whether Yarsagumba extract and cordycepin possess anti-proliferative and vasorelaxant properties in the context of PH, using 5-bromo-2’-deoxyuridine assay and isolated mice lungs, respectively. Results: Our results revealed that Yarsagumba extract and its bioactive compound cordycepin significantly attenuated the proliferation of human pulmonary artery smooth muscle cells derived from donor and PH subjects. In isolated murine lungs, only Yarsagumba extract, but not cordycepin, resulted in vasodilatation, indicating the probable existence of other bioactive metabolites present in Yarsagumba that may be responsible for this outcome. Conclusion: Future comprehensive in vivo and in vitro research is crucially needed to discover the profound mechanistic insights with regard to this promising therapeutic potency of Yarsagumba extract and to provide further evidence as to whether it can be used as a strategy for the treatment of PH