Regulation of Blood Pressure Circadian Rhythm by Vascular Smooth Muscle BMAL1

描述（由申请人提供）：众所周知的血压（BP）昼夜节律对人类健康很重要，糖尿病患者的BP昼夜节律紊乱正在成为未来靶器官损伤和心血管结局的指标。最近的发现表明，生物钟基因在所有被研究的组织中都有表达，这挑战了BP昼夜节律完全由中枢起搏器控制的教条。然而，它是完全未知的特定的时钟基因在外周组织是重要的血压昼夜节律。我们已经产生了一种新的平滑肌特异性时钟基因BMAL 1敲除小鼠SM-bmal 1-/-，以研究在生理和糖尿病条件下血管平滑肌在血压昼夜节律中的作用。我们发现，血管平滑肌BMAL 1是必不可少的正常血压昼夜节律以及正常血管平滑肌收缩昼夜变化。此外，我们的初步研究表明rho激酶ROCK 2将BMAL 1与收缩联系起来。重要的是，我们发现，在2型糖尿病db/db小鼠中，BMAL 1蛋白和活性昼夜振荡的丧失与血管平滑肌昼夜变化和BP昼夜节律的丧失相关。因此，我们假设BMAL 1调节ROCK 2，从而控制血管平滑肌收缩的昼夜节律变化，从而显著促进正常血压昼夜节律及其在糖尿病中的破坏。我们建议使用体外和体内的方法来测试在三个特定的目标的假设：1）测试的假设，在生理条件下，BMAL 1调节血管平滑肌收缩昼夜节律的变化和血压昼夜节律通过ROCK 2。2)检验以下假设：在糖尿病条件下，BMAL 1是破坏血管平滑肌收缩昼夜节律变化所必需的。3)确定血管平滑肌BMAL 1在糖尿病相关血压昼夜节律紊乱中的作用。从拟议的研究结果可能会修改的教条，中央起搏器是唯一负责的生理BP昼夜节律提供了第一个直接的实验证据，外周血管平滑肌BMAL 1发挥重要作用。此外，我们的研究结果可能通过提供以下证据将血管平滑肌BMAL 1确定为控制糖尿病患者24小时血压的潜在治疗靶点： BMAL 1是糖尿病与血压昼夜节律紊乱之间的重要联系。

DESCRIPTION (provided by applicant): The well-known blood pressure (BP) circadian rhythm is important to human health and BP circadian rhythm disruption in diabetes is emerging as an index for future target organ damage and cardiovascular outcomes. Recent discoveries that clock genes are expressed in all of the tissues examined challenges the dogma that BP circadian rhythm is solely controlled by central pacemaker. However, it is completely unknown which specific clock gene(s) in which peripheral tissue(s) are important for BP circadian rhythm. We have generated a novel smooth muscle specific clock gene BMAL1 knockout mice SM-bmal1-/- to investigate the role of vascular smooth muscle in BP circadian rhythm under physiological and diabetic conditions. We found that vascular smooth muscle BMAL1 is essential for normal BP circadian rhythm as well as normal vascular smooth muscle contractile circadian variation. Moreover, our preliminary study implicates rho kinase, ROCK2, links BMAL1 to contraction. Importantly, we found that, in type 2 diabetic db/db mice, loss of BMAL1 protein and activity circadian oscillations is associated with loss of vascular smooth muscle circadian variation and BP circadian rhythm. Thus we hypothesize that BMAL1 regulates ROCK2, thus controlling vascular smooth muscle contractile circadian variation, thereby significantly contributing to normal BP circadian rhythm and its disruption in diabetes. We propose to use in vitro and in vivo approaches to test the hypothesis in three specific aims: 1) test the hypothesis that, under physiological conditions, BMAL1 regulates the vascular smooth muscle contractile circadian variation and BP circadian rhythm via ROCK2. 2) Test the hypothesis that, under diabetic conditions, BMAL1 is required for disruptions in vascular smooth muscle contractile circadian variation. 3) Determine the role of vascular smooth muscle BMAL1 in diabetes-associated disruption of BP circadian rhythm. Results from the proposed studies may modify the dogma that central pacemaker is solely responsible for the physiological BP circadian rhythm by providing the first direct experimental evidence that peripheral vascular smooth muscle BMAL1 play an important role. Moreover, our results may identify vascular smooth muscle BMAL1 as a potential therapeutic target for control of 24-h BP in diabetic patients by providing evidence that BMAL1 is a significant contributor linking diabetes to disruptions of BP circadian rhythm.