Abstract
Vascular remodeling is considered a key event in the pathogenesis of pulmonary arterial hypertension (PAH). However, mechanisms of gaining the proliferative phenotype by pulmonary vascular cells are still unresolved. Due to well-established pyruvate dehydrogenase (PDH) deficiency in PAH pathogenesis, we hypothesized that the activation of another branch of pyruvate metabolism, anaplerosis, via pyruvate carboxylase (PC) could be a key contributor to the metabolic reprogramming of the vasculature. In sugen/hypoxic PAH rats, vascular proliferation was found to be accompanied by increased activation of Akt signaling, which upregulated membrane Glut4 translocation and caused upregulation of hexokinase and pyruvate kinase-2, and an overall increase in the glycolytic flux. Decreased PDH activity and upregulation of PC shuttled more pyruvate to oxaloacetate. This results in the anaplerotic reprogramming of lung vascular cells and their subsequent proliferation. Treatment of sugen/hypoxia rats with the PC inhibitor, phenylacetic acid 20 mg/kg, starting after one week from disease induction, significantly attenuated right ventricular systolic pressure, Fulton index, and pulmonary vascular cell proliferation. PC inhibition reduced the glycolytic shift by attenuating Akt-signaling, glycolysis, and restored mitochondrial pyruvate oxidation. Our findings suggest that targeting PC mediated anaplerosis is a potential therapeutic intervention for the resolution of vascular remodeling in PAH.
Highlights
Pulmonary arterial hypertension (PAH) is considered as a fatal vascular disease progressing to right ventricular (RV) dysfunction and failure if untreated
De-identified human plasma samples consisted of patients with a diagnosis of diabetes mellitus (DM) group (N = 12), left heart disease (HD) group (N = 11), and idiopathic pulmonary arterial hypertension (IPAH) group (N = 11) were obtained through the Center for Disparities in Diabetes, Obesity and Metabolism and Health Sciences Biorepository at the University of Arizona, and from Pulmonary Hypertension Breakthrough Initiative (PHBI)
Increased Right ventricular systolic pressure (RVSP) showed a significant correlation with the Fulton index (Figure 1C). dP/dtmax is a measure of myocardial contractility was increased SU5 PAH group, but the pyruvate carboxylase (PC) inhibitor treatment significantly improved cardiac function and prevented further increase in dP/dtmax (Figure 1D)
Summary
Pulmonary arterial hypertension (PAH) is considered as a fatal vascular disease progressing to right ventricular (RV) dysfunction and failure if untreated. In PAH, vascular remodeling and proliferative changes narrow the lumen of pulmonary arteries, causing increased vascular resistance [1]. Pulmonary vascular cell dysfunction is considered as an initiator on the pathogenesis of PAH [3]. In PAH pathogenesis, understanding the molecular mechanisms that initiate vascular cell transition to a highly proliferative phenotype, could help for earlier diagnostics and improve the treatment of PAH. The sustained activity of the TCA cycle needs the supplementation of carbon intermediates. We hypothesize that inhibition of PC could prevent anaplerotic reprogramming and vascular proliferation in pulmonary vascular cells and this could attenuate PAH pathogenesis.
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