Abstract 16758: The Role of Estrogen Receptor Alpha in Preserving Right Ventricular Mitochondrial Respiration in Pressure Overload

Abstract

Background: Pulmonary arterial hypertension (PAH) occurs more often in women, but women exhibit better survival. Rodent models of PAH suggest a right ventricular (RV) protective effect of estrogen signaling through estrogen receptor alpha (ERα). While estrogen regulates mitochondrial biogenesis and function, the role of ERα in preserving RV mitochondrial function in the setting of pressure overload is unknown. Methods: Estrogen receptor alpha knockout (ERKO) rats were created using a CRISPR/Cas9 system. Male and female ERKO and littermate control (WT) rats underwent pulmonary artery banding (PAB) or sham surgery. After 10 weeks, RV systolic pressure (RVSP) and contractility as measured by dP/dt max were recorded by open-chest right heart catheterization. RV hypertrophy was measured by normalizing RV free wall weight to tibia length (TL). Permeabilized muscle fibers from the RV were placed in a high-resolution respirometer in the presence of substrates and inhibitors to measure mitochondrial respiration. Results: PAB caused a greater increase in RVSP (Fig. A) and contractility (Fig. B) in the ERKO compared to WT rats. WT and ERKO had comparable degrees of RV hypertrophy (Fig. C). RV muscle fiber respiratory control ratio (RCR) demonstrated a significant positive correlation with RVSP in ERKO rats (Fig. D) not found in WT rats, suggesting that pressure overload is associated with enhanced mitochondrial coupling in the absence of ERα. A decrease in State 4 ADP-depleted respiration in ERKO rats (Fig. E) accounts for the decrease in RCR. PAB did not alter Complex II or Complex IV respiration in either ERKO or WT rats. Conclusions: Whereas in the presence of ERα RV adaptation to pressure overload is independent of mitochondrial respiration changes, in the absence of ERα, pressure overload decreased State 4 ADP-depleted respiration, suggesting that ERα regulates RV mechanoenergetic remodeling due to pressure overload.