Moderate Chronic Ethanol Consumption Provokes Pulmonary Arterial Hypertension in Male Rats

Abstract

Significant attention is dedicated to studying ethanol and the effect it elicits on left-side heart function and systemic blood pressure, ignoring its cardiopulmonary impact, specifically in relation to pulmonary arterial hypertension (PAH). Using male Sprague-Dawley (SD) rats, this study was designed to address this concern in three phases: 1) Analyzing the cardiopulmonary effects of chronic ethanol consumption; 2) Assessing PAH induction via vascular endothelial growth factor (VEGF) receptor inhibition by SU5415 (SU) injection; 3) Evaluating chronic ethanol consumption and its effect in PAH induced by VEGF receptor blockade. Designed to elucidate ethanol's hemodynamic, structural, and molecular effects on cardiopulmonary health in healthy and diseased rats, the overarching hypothesis of this preclinical study was that chronic ethanol consumption predisposes and exacerbates PAH pathophysiology through upregulation of the endothelin-/tumor necrosis factor-a/interleukin-6 (ET-1/TNF-a/IL-6) vasoconstricting/pro-inflammatory signaling axis and subsequent downregulation of cardioprotective bone morphogenetic protein receptor 2 (BMPR2). Our research demonstrates ethanol alone causes cardiopulmonary remodeling, inflammation, and cardioprotective receptor modulation similar to that of the PAH-inducing injection (SU). Additional observations found that ethanol consumption exacerbates the PAH pathology in male rats with SU-induced PAH, causing increased right ventricle (RV) and left ventricle (LV) hypertrophy, elevated mean pulmonary arterial pressure (mPAP) and mean arterial pressure (MAP), and significant RV fibrosis. Collectively, these results support our hypothesis that chronic ethanol consumption is a cardiopulmonary insult, predisposing and exacerbating PAH pathophysiology.