MEF2 and the Right Ventricle: From Development to Disease

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.

Keywords: HDAC; MEF2; hypertrophy; pulmonary hypertension; right ventricle.

Figure 1

Right ventricular (RV) adaptation in pulmonary hypertension. In response to increasing pulmonary arterial (PA) pressure, the RV hypertrophies and augments its contractility (RV-PA coupling is maintained). This adaptive RV hypertrophic response is mediated in part by MEF2C with expression of MEF2 targets such as GLUT4, ANF, and aMHC. However, with a progressive increase in RV afterload the RV dilates, increasing the free wall stress and myocardial oxygen consumption. Consequently, the RV-PA unit is uncoupled. During this decompensated phase, there is a decrease in MEF2C levels, which is linked to mir208 suppression and increased MED13/NCoR1 activity. NCoR1 is known to decrease Mef2c transcription and acts in a complex with HDAC3/4 to deacetylate MEF2D and decrease its activity. MEF2C, myocyte enhancer factor 2C; miR, microRNA.

Figure 2

Alteration of the pulmonary vascular endothelium in pulmonary arterial hypertension (PAH). In the normal pulmonary vasculature, MEF2 promotes endothelial function preserving vessel density. In PAH, downregulation of MEF2 from increased nuclear localization of HDAC4 and HDAC5 results in decreased MEF2 activity and decreased expression of antiproliferative miR-424 and miR-503, the vascular homeostatic factors connexins 37, 40, and the anti-inflammatory and antithrombotic KLF2 and KLF4. These molecular alterations then lead to abnormal endothelial cell proliferation and muscularization of the pulmonary arterioles. MEF2, myocyte enhancer factor; HDAC, histone deacetylase; mir, micro ribonucleic acid.