Endogenous mechanism of right ventricular repair in pulmonary hypertension

Abstract

IntroductionRight‐sided heart failure is the major cause of death among patients with pulmonary hypertension (PH) as well as children who suffer from various forms of congenital heart disease. Thus, agents that repair the damaged right ventricle (RV) have therapeutic potential to treat right‐sided heart failure. The biology of RV, however, is not well understood. The present study describes an endogenous mechanism for RV repair that was discovered in an experimental animal model of PH.Methods & ResultsThe treatment of Sprague‐Dawley (SD) rats with the injection of SU5416 (VEGF inhibitor) and 3 weeks of chronic hypoxia, followed by the maintenance in normoxia, resulted in progressive PH and RV remodeling. At 17 weeks after the initiation of the treatment, RV cardiomyocytes were damaged and the fibrotic region was found to be 12% of the total RV. However, at 35 weeks, RV fibrosis was significantly reduced and new cardiomyocytes were regenerated, despite RV pressure remained elevated. Before the RV repair occurs, α‐smooth muscle actin (αSMA) was found to be expressed in myofibroblasts. In addition, we noted the expression of αSMA in some of RV cardiomyocytes. Normal terminally differentiated cardiomyocytes do not express αSMA, but induced cardiomyocytes (iCMs) derived from induced pluripotent stem cells (iPSCs) do. Thus, we hypothesized that the damaged RV is repaired by activating the cellular reprogramming process that converts resident cardiac fibroblasts into iCMs perhaps through an iPSC‐like mechanism. This hypothesis was substantiated by our observations that Sox2, stem cell‐specific transcription factor, was also expressed in RV cardiomyocytes being repaired. Further, transmission electron microscopy observations revealed that extracellular matrix contains fibroblast‐line cells with myofilaments, which are organized into myofibrils and formed into the sarcomere‐like structure similar to iCMs.ConclusionsThe RV damage promoted by PAH can be repaired through a naturally occurring process that may involve cardiomyocyte regeneration through cell reprogramming. Understanding such an endogenous repair mechanism should contribute to the development of therapeutic strategies to treat right‐sided heart failure.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.