Angiotensin II Induces Circadian Gene Expression of Clock Genes in Cultured Vascular Smooth Muscle Cells

Abstract

Background-Daily rhythms of mammalian physiology and endocrinology are regulated by circadian pacemakers. The master circadian pacemaker resides in the suprachiasmatic nucleus, which is located in the hypothalamus of the brain, but circadian oscillators also exist in peripheral tissues. Because many studies have demonstrated apparent circadian variations in the frequency of cardiovascular disorders, it is of great interest to investigate a possible relation between circadian gene expression and cardiovascular function. We examined whether a circadian oscillation system exists in the aorta and/or in cultured vascular smooth muscle cells (VSMCs). Methods and Results-The mRNA levels of clock genes were assayed by northern blot analysis. The mouse aorta showed a clear circadian oscillation in the expression of mPer2, dbp, and Bmal1. Brief treatment of VSMCs with angiotensin II induced a robust increase in mPer2 gene expression, followed by a marked reduction in mPer2 mRNA levels and subsequent synchronous cycling of mPer2, dbp, and Bmal1 mRNAs. The induction of mPer2 in VSMCs by angiotensin II was completely abolished by treatment with CV11947, a specific angiotensin II type1 receptor antagonist. Conclusions-The present results demonstrate that the aorta and VSMCs possess a circadian oscillation system which is comparable to that of the suprachiasmatic nucleus and that the circadian gene expression in VSMCs is induced by angiotensin II through the angiotensin II type1 receptor. Our in vitro system will provide a useful tool to further analyze the physiological significance of the peripheral clock in cardiovascular function. Key Words: angiotensin Ⅲ circadian rhythm Ⅲ molecular biology Ⅲ muscle, smooth I n mammals, behavioral and physiological processes display Ϸ24-hour rhythms that are regulated by circadian pacemakers. On the basis of surgical ablation and transplantation experiments, the central circadian pacemaker is thought to reside in the hypothalamic suprachiasmatic nucleus. 1 However, several lines of evidence indicate that peripheral tissues and immortalized cells also contain circadian oscillators; the molecular mechanisms of these oscillators are virtually identical to those in the suprachiasmatic nucleus. [2][3][4][5] The molecular mechanism of this circadian oscillator is based on interacting transcriptional-translational autoregulatory feedback loops. The feedback loop involves 3 homologs of the Drosophila gene period (mPer1, mPer2, and mPer3) and 2 cryptochrome genes (mCry1 and mCry2). The rhythmic transcription of the mPer and mCry genes is driven by the transcription activator genes Clock and Bmal1. 6 Various cardiovascular functions, including blood pressure, heart rate, and coagulation parameters, are known to show a diurnal variation. 7 In addition, several cardiovascular events, such as myocardial infarction, sudden cardiac death, and stroke, show well-defined patterns in their occurrence throughout the day. 8 Although such diurnal variations are widely known, the underlying molecular mechanisms...

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