Impact of cardiosphere-derived cells on the maladapted right ventricular muscle in a rat sugen/hypoxia model of pulmonary hypertension with right ventricular dysfunction

Abstract

Background and aims With pulmonary arterial hypertension (PAH), right ventricular (RV) function is a major determinant of survival. Despite current therapies, maladaptive changes ensue in the RV muscle of PAH patients, culminating in RV dysfunction and failure. The aims of the study were to evaluate the impact of intra-coronary (IC) cardiosphere-derived cells (CDCs) in attenuating the maladaptive pathobiology in the RV muscle and evaluating mechanisms underlying improvements in RV function. Methods Two groups of the Sugen/Hypoxia rat model of PAH, exhibiting significantly reduced RV function, via TAPSE measurements, received either intracoronary infusion of CDCs or PBS placebo. Immunohistochemistry methods were used to assess RV pathobiological changes. Additionally, advanced proteomics were employed to examine protein signaling pathways and upstream regulators. Results RV muscle capillarity was significantly reduced in the PAH rats while RV muscle fibrosis was increased. IC CDCs significantly increased RV muscle capillarity back to levels noted in healthy rats and reduced RV free wall fibrosis. Further, a significant reduction in iNOS+ (M1) macrophages was also observed within the RV free wall in CDC-treated animals. Proteomic analysis of RV muscle in CDC- or PBS-treated PAH rats showed alterations in protein pathways related to inflammation, fibrosis, autophagy, cell vitality, and angiogenesis. These changes were consistent with putative coordination by a small number of key upstream regulators (MYC, TP53, HNF4A, TGFB1, and KRAS). TAPSE was significantly reduced in PBS-treated animals but was maintained at or above baseline levels in CDC-treated animals. Conclusions CDC therapy can significantly impact the maladaptive milieu of the RV myocardium in advanced PAH, by altering several pathobiological pathways. Such adjunctive therapy, in addition to those employed to reduce pulmonary vascular resistance, would be a great advance in managing RV failure, for which no effective current approved therapies exist.