Alcohol suppresses cardiovascular diurnal variations in male normotensive rats: Role of reduced PER2 expression and CYP2E1 hyperactivity in the heart.

Abstract

The molecular mechanism of the adverse effects of ethanol on diurnal cardiovascular regulation remains unknown. In separate studies, the cardiac circadian rhythm protein period-2 (PER2) confers cardioprotection and, in other organs, PER2 interaction with the ethanol-metabolizing enzyme CYP2E1 underlies, via heme oxygenase-1 (HO-1) upregulation, tissue injury/dysfunction. Here, we hypothesized that suppressed PER2 expression and elevated CYP2E1/HO-1 levels in the heart underlie the disrupted diurnal cardiovascular rhythm/function in alcohol-fed normotensive rats. In ethanol-fed (5%, w/v; 8 weeks) or isocaloric liquid diet-fed male rats, diurnal changes in blood pressure (BP), heart rate (HR), HR vagal variability index, root mean square of successive beat-to-beat differences in beat-interval duration (rMSSD), and cardiac function were measured by radiotelemetry and echocardiography followed by exvivo molecular studies. Radiotelemetry findings showed ethanol-evoked reductions in BP (during the dark cycle), rMSSD (during both cycles), and in diurnal differences in BP and rMSSD. Echocardiography findings revealed significant (p<0.05) reductions in ejection fraction and fractional shortening (weeks 4-6) in the absence of cardiac remodeling (collagen content). Hearts of ethanol-fed rats exhibited higher (p<0.05) CYP2E1 activity (50%) and HO-1 expression (63%), along with reduction (p<0.05) in PER2 levels (29%), compared with the hearts of isocaloric diet-fed control rats. Our novel findings implicate upregulations of CYP2E1/HO-1 and downregulation of the circadian rhythm cardioprotective protein PER2, in the heart, in the chronic deleterious diurnal cardiovascular effects of alcohol in male rats.