Abstract 4141399: Chronic Moderate Alcohol Consumption In ApoE ^-/- Mice Impaires Vascular Endothelial Function Through Redox Dysregulation of Rac1

Background: Chronic alcohol consumption is known to impair endothelial function and contribute to cardiovascular disease. However, the effects of moderate alcohol consumption on vascular function, especially in the presence of atherogenic risk factors like hypercholesterolemia, remain inconsistent and unclear. Methods and Results: To simulate chronic moderate and heavy drinking in hypercholesterolemic conditions, ApoE deficient (ApoE−/−) mice were fed a Lieber-DeCarli liquid diet with ethanol (2g/kg/day for moderate and 5g/kg/day for heavy drinking) or isocaloric maltose (5g/kg/day as control) for 12 weeks. In vivo flow-mediated vasodilation (FMD) of the femoral artery was assessed at 6 and 10 weeks. Both moderate and heavy alcohol consumption significantly impaired endothelium-dependent FMD, while endothelium-independent FMD increased after 10 weeks, indicated by higher FMD values in the presence of L-NAME, an eNOS inhibitor. Moderate and heavy drinking also promoted aortic endothelial permeability (measured by Evan’s blue dye infiltration) and atherosclerotic lesions at the aortic root. In aorta and endothelium-rich lung tissues, protein S-glutathionylation levels were elevated in both drinking groups, coinciding with eNOS inactivation (reduced dimer to monomer ratio), impaired Rac1 RhoGTPase activity, and increased Rac1 glutathionylation. In human aortic endothelial cells, ethanol exposure dose-dependently promoted protein S-glutathionylation and lowered glutaredoxin-1 (Grx1) levels. Moderate ethanol treatment (25mM) alone had negligible impact on eNOS and Rac1 activities but caused endothelial dysfunction under metabolic stress or Grx1 knockdown, mirroring animal study findings. Conclusions: This study provides evidence that moderate alcohol consumption can cause vascular endothelial dysfunction in the presence of hypercholesterolemia. The underlying mechanism involves S-glutathionylation-centered redox dysregulation of Rac1 and eNOS.