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.

Public Health Relevance

The well-known blood pressure (BP) circadian rhythm is important for human health and the disruption of BP circadian rhythm in diabetes is emerging as an index of future target organ damage and cardiovascular outcomes. However, molecular mechanisms linking diabetes with disruption in BP circadian rhythm are unknown. The goals of this application are to elucidate the molecular mechanisms responsible for normal BP circadian rhythm and its disruptions in diabetes.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL106843-03
Application #
8658139
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Laposky, Aaron D
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Lexington
State
KY
Country
United States
Zip Code
40506
Liu, Shu; Xie, Zhongwen; Daugherty, Alan et al. (2013) Mineralocorticoid receptor agonists induce mouse aortic aneurysm formation and rupture in the presence of high salt. Arterioscler Thromb Vasc Biol 33:1568-79