Temporal Changes in Key Signal Transduction Pathways Mediating Muscle Protein Synthesis with Adaptive and Maladaptive Right Ventricular Hypertrophy in Pulmonary Arterial Hypertension

Abstract

Pulmonary Arterial Hypertension (PAH) is a progressive disease characterized by occlusive remodeling of pulmonary arteries < 500 micron and increased pulmonary vascular resistance. With the onset of PAH, the right ventricle (RV) of the heart adapts to the increased afterload pressure by undergoing adaptive hypertrophic remodeling to maintain adequate blood flow. However, for unknown reasons, maladaptive influences ensue, resulting in impaired RV function with progressive decompensation and right heart failure. Using a rodent model of PAH, key signaling pathways mediating cardiac muscle protein synthesis in the RV were evaluated during both the adaptive hypertrophy phase, with preserved right heart function, and the decompensated maladaptive phase, in which right heart failure (RHF) was present. Analysis of protein and gene expression changes in PAH animals identified three key signaling pathways involved in the shift toward maladaptive right heart failure: i) PI3K/Akt/mTOR; ii) GSK-3; iii) MAPK/ERK, as well as IGF-1 regulation. During adaptive hypertrophy, significant increments of phosphorylated proteins in the three signaling pathways were observed with increases in RV fibrosis and decreased capillarity found. In the maladaptive phase, mTORC1 and its downstream effector p-70S6K were significantly activated, contributing to the decreased LC3-I/II ratio, a marker of autophagy inhibition together with further significant RV muscle fibrosis and greater capillary rarefaction. We propose that autophagy inhibition in conjunction with other maladaptive processes reported in the decompensated RV muscle contributes to the genesis of overt RHF in PAH, and that a continuum of changes characterizes the adaptive and maladaptive phases in the RV muscle Keywords: Pulmonary Arterial Hypertension (P