Clock Gene Bmal1 Disruption in Vascular Smooth Muscle Cells Worsens Carotid Atherosclerotic Lesions

Changpo Lin; Lirong Xu; Xiao Tang; Xiaobo Li; Chao Lu; Qianyun Cheng; Junhao Jiang; Yang Shen; Dong Yan; Ruizhe Qian; Weiguo Fu; Daqiao Guo

doi:10.1161/ATVBAHA.121.316480

Clock Gene Bmal1 Disruption in Vascular Smooth Muscle Cells Worsens Carotid Atherosclerotic Lesions

Arterioscler Thromb Vasc Biol. 2022 May;42(5):565-579. doi: 10.1161/ATVBAHA.121.316480. Epub 2022 Mar 3.

Authors

Changpo Lin^#^{1

2

3}, Lirong Xu^#^{2

3}, Xiao Tang^#¹, Xiaobo Li^{4

5}, Chao Lu⁵, Qianyun Cheng⁵, Junhao Jiang^{1

2

3}, Yang Shen^{1

2

3}, Dong Yan^{1

2

3}, Ruizhe Qian⁵, Weiguo Fu^{1

2

3}, Daqiao Guo^{1

2

3}

Affiliations

¹ Department of Vascular Surgery, Institute of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China (C.L., X.T., J.J., Y.S., D.Y., W.F., D.G.).
² National Clinical Research Center for Interventional Medicine, Shanghai, China (C.L., X.T., J.J., Y.S., D.Y., W.F., D.G.).
³ Shanghai Clinical Research Center for Interventional Medicine, China (C.L., X.T., J.J., Y.S., D.Y., W.F., D.G.).
⁴ Department of Pathology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, China (L.X.).
⁵ Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, China (X.L., C.L., Q.C., R.Q.).

^# Contributed equally.

PMID: 35236106
DOI: 10.1161/ATVBAHA.121.316480

Abstract

Background: Clock system disruptions are associated with cardiovascular diseases. We previously demonstrated Bmal1 (brain muscle aryl nuclear translocase like-1) expression is significantly attenuated in plaque-derived vascular smooth muscle cells (VSMCs). However, the influence of Bmal1 disruption in VSMCs and its molecular targets are still unclear. Here, we aim to define how Bmal1 disruption in VSMCs influences the atherosclerosis lesions.

Methods: The relationship among Bmal1, neurological symptoms, and plaque stability was investigated. VSMC Bmal1^-/- and VSMC Bmal1^+/+mice were generated and injected with adeno associated virus encoding mutant proprotein convertase subtilisin/kexin type 9 to induce atherosclerosis. Carotid artery ligation and cuff placement were performed in these mice to confirm the role of Bmal1 in atherosclerosis progression. The relevant molecular mechanisms were then explored.

Results: Bmal1 expression in the carotid plague was significantly lower in symptomatic patients as well as in unstable plaques. Moreover, Bmal1 reduction is an independent risk factor for neurological symptoms and plaque instability. Besides, VSMC Bmal1^-/- mice exhibit aggravated atherosclerotic lesions. Further study demonstrated that Bmal1 downregulation in VSMCs increased VSMC migration, monocyte transmigration, reactive oxygen species levels, and VSMCs apoptosis. As for the mechanism, we revealed that Bmal1 suppresses VSMCs migration by inhibiting RAC1 activity in 2 ways: by activating the transcription of RhoGDIα and by interacting with RAC1. Besides, Bmal1 was shown to preserve antioxidant function in VSMCs by activating Nrf2 (nuclear factor erythroid 2-related factor 2) and Bcl-2 transcription.

Conclusions: Bmal1 disruption in VSMCs worsens atherosclerosis by promoting VSMC migration and monocyte transmigration and impairing antioxidant function. Therefore, Bmal1 may be a potential therapeutic target and biomarker of atherosclerosis in the future.

Keywords: apoptosis; atherosclerosis; cardiovascular diseases; cell migration; circadian clocks; reactive oxygen species; smooth muscle cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antioxidants / metabolism
Atherosclerosis* / pathology
Carotid Arteries / pathology
Cells, Cultured
Humans
Mice
Muscle, Smooth, Vascular / metabolism
Myocytes, Smooth Muscle / metabolism
Plaque, Atherosclerotic* / pathology

Substances

Antioxidants