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

Abstract

BackgroundPulmonary Arterial Hypertension (PAH) is a progressive cardiopulmonary disease and is characterized by occlusive remodeling of pulmonary arterioles 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, we evaluated key signaling pathways mediating cardiac muscle protein synthesis in the RV during the adaptive hypertrophy phase, with preserved right heart function, and the decompensated maladaptive phase, in which right heart failure (RHF) was clinically present.MethodsMale Sprague-Dawley rats were injected subcutaneously with 60mg/kg Monocrotaline (MCT) and RV function was assessed by echocardiography during PAH disease progression. RV tissue was collected during the adaptive and maladaptive phases of PAH and cell signaling pathways involved in survival, hypertrophy, and autophagy, as well as fibrosis and vascularization, were probed using qPCR, Western blotting and histology. Statistical analysis was performed using ANOVA to compare differences between the independent groups and Student-Newman-Keuls test was used to compare differences within independent groups.ResultsAnalysis 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. Additionally, p27, a cyclin-dependent kinase (CDK) inhibitor, which has been recently implicated in regulating mTOR activity to inhibit autophagy and promote heart failure was significantly downregulated. ConclusionWe 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.