Background and aims

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.

Methods

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 ex vivo molecular studies.

Results

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.

Conclusions

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.

中文翻译：

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酒精抑制雄性血压正常大鼠的心血管昼夜变化：心脏中 PER2 表达降低和 CYP2E1 过度活跃的作用。

背景和目标

乙醇对昼夜心血管调节不利影响的分子机制尚不清楚。在单独的研究中，心脏昼夜节律蛋白 period-2 (PER2) 赋予心脏保护作用，并且在其他器官中，PER2 与乙醇代谢酶 CYP2E1 相互作用，通过血红素加氧酶-1 (HO-1) 上调、组织损伤/功能障碍. 在这里，我们假设抑制 PER2 表达和升高心脏中的 CYP2E1/HO-1 水平是酒精喂养的正常血压大鼠昼夜心血管节律/功能紊乱的基础。

方法

在乙醇喂养（5%，w/v；8 周）或等热量液体饮食喂养的雄性大鼠中，血压 (BP)、心率 (HR)、HR 迷走神经变异指数、连续搏动的均方根的昼夜变化通过无线电遥测和超声心动图测量心跳间隔持续时间 (rMSSD) 和心脏功能的差异，然后进行体外分子研究。

结果

无线电遥测结果显示乙醇引起的血压降低（在黑暗循环期间）、rMSSD（在两个循环期间）以及 BP 和 rMSSD 的昼夜差异。超声心动图结果显示 ，在没有心脏重塑（胶原含量）的情况下，射血分数和缩短分数（第 4-6 周）显着降低（p < 0.05）。与对照组相比，乙醇喂养大鼠的心脏表现出更高 ( p  < 0.05) CYP2E1 活性 (50%) 和 HO-1 表达 (63%)，同时 PER2 水平 (29%)降低 ( p < 0.05)。等热量饮食喂养的对照大鼠。

结论

我们的新发现表明，酒精对雄性大鼠的慢性有害昼夜心血管影响中，CYP2E1/HO-1 的上调和心脏中昼夜节律心脏保护蛋白 PER2 的下调。