Abstract 118: Methamphetamine Causes Endothelial Dysfunction Via Reduction Of Cystathionine Gamma Lyase And Hydrogen Sulfide Bioavailability

Abstract

Background: Methamphetamine (METH) is an addictive illicit drug used worldwide that can elicit significant damage on blood vessels resulting in increased inflammation and cardiovascular dysfunction. Recent studies highlight increased prevalence of cardiovascular disease (CVD) and associated complications including hypertension, vasospasm, left ventricular hypertrophy, and coronary artery disease in younger populations due to METH use making cardiovascular complications the second leading cause of death in METH substance users. The purpose of this study is to understand the underlying molecular mechanisms of METH-related cardiovascular injury. Methods and Results: Here we report that METH administration in a mouse model of ‘binge and crash’ decreases vascular function through a CSE/H 2 S/NO-dependent pathway. METH significantly reduced H 2 S and NO bioavailability in plasma and skeletal muscle tissues co-incident with a significant reduction in flow-mediated vasodilation (FMD) and blood flow velocity highlighting endothelial dysfunction. METH administration also reduced cardiac ejection fraction (EF) and fractional shortening (FS) indicating pump dysfunction. Interestingly, METH treatment selectively decreased CSE expression co-incident with reduced eNOS phosphorylation. Importantly, either exogenous H 2 S therapy or endothelial CSE transgenic overexpression corrected endothelial dysfunction and associated pathological responses due to METH toxicity. Conclusions: Our results uniquely demonstrate that METH mediates reduction of CSE expression and activity in endothelial cells, and subsequent attenuation of H 2 S/NO bioavailability directly leading to impaired cardiac and vascular function. Exogenous sulfide therapy or endothelial CSE transgenic overexpression rescues METH-induced vascular dysfunction.