MEF2 and the Right Ventricle: From Development to Disease.

Katharine R Clapham,Inderjit Singh,Isabella S Capuano,Sudarshan Rajagopal,Hyung J Chun

doi:10.3389/fcvm.2019.00029

Abstract

Pulmonary arterial hypertension is a progressive and ultimately life-limiting disease in which survival is closely linked to right ventricular function. The right ventricle remains relatively understudied, as it is known to have key developmental and structural differences from the left ventricle. Here, we will highlight what is known about the right ventricle in normal physiology and in the disease state of pulmonary arterial hypertension. Specifically, we will explore the role of the family of MEF2 (myocyte enhancer factor 2) transcription factors in right ventricular development, its response to increased afterload, and in the endothelial dysfunction that characterizes pulmonary arterial hypertension. Finally, we will turn to review potentially novel therapeutic strategies targeting these pathways.

Highlights

Pulmonary arterial hypertension (PAH) remains a significant therapeutic challenge, despite ongoing advances in our body of knowledge of this devastating disease
The initial response of the right ventricular (RV) to a chronic increase in afterload is to increase its contractile reserve to match the increasing afterload. This homeometric adaptation is achieved through RV myocyte hypertrophy leading to a concentric remodeling pattern, which is characterized by a higher mass-to-volume ratio that allows for preservation of RV contractile function [13]
The available evidence suggests that MEF2C may initially serve to promote an adaptive hypertrophic response to increased afterload in the RV, but that there is a shift to proapoptotic, fibrotic, and glycolytic pathways during decompensation that is associated with decreased MEF2 activity [56, 57] (Figure 1)

Summary

INTRODUCTION

Pulmonary arterial hypertension (PAH) remains a significant therapeutic challenge, despite ongoing advances in our body of knowledge of this devastating disease. No approved therapies to date seek to directly achieve improvement or preservation of the right ventricular (RV) function, despite compelling evidence that RV function is a critical determinant of clinical outcomes in PAH. Recent studies have begun to investigate strategies to preserve or improve RV function in the context of increased pulmonary vascular resistance (PVR), including application of left-sided heart failure treatments to RV failure. In this review we discuss what is known about mechanisms of RV development and disease, and highlight recent advances that may lead to novel RV-based therapeutic strategies

THE NORMAL RV

RV ADAPTATION TO PAH

Absent Reduced perfusion

ALTERATIONS IN RV METABOLISM

RV DEVELOPMENT

CONCLUSION