Pro-oxidative Mitochondrial Metabolism of Bovine Arterial Wall Fibroblasts in Pulmonary Hypertension Syndrome can be Reversed by PTBP1 Silencing and Histone Deacetylase Inhibition

Abstract

Pulmonary arterial hypertension (PH) is a serious complex disease often leading to heart failure and early death of patients. We and others have previously demonstrated that pulmonary adventitial fibroblasts from chronically hypoxic hypertensive calves (PH-Fibs) exhibit a highly proliferative, migratory, pro-inflammatory, and apoptosis-resistant phenotype similar to cancer cells. As in many cancer cells this is accompanied by a constitutive metabolic shift manifesting increased glycolysis, mainly due to increased expression ratio of pyruvate kinase M2/1 isoforms, lowered mitochondrial respiration and enhanced superoxide production[1], we focused on the regulation of an altered mitochondrial function in PH-Fibs by miR-124 and polypyrimidine tract binding protein 1 (PTBP1). Measuring membrane potential, respiratory parameters, Complex I function and redox status, we found that either miR-124 addition or PTBP1 silencing is capable to rescue mitochondrial function and superoxide production of PH-Fibs towards control fibroblasts (CO-Fibs) levels. Moreover, further regulation of the mitochondrial metabolism switch in PH-Fibs by class I histone deacetylase (HDAC) was proven. Our data reveal novel mechanisms and possible approaches how to reverse mitochondrial metabolic reprogramming of PH-Fibs which can result in potential future therapeutic employment.