Aging
Navigate
Submit an Article
Research Paper|Volume 13, Issue 11|pp 14892—14909

Inhibition of CDK9 attenuates atherosclerosis by inhibiting inflammation and phenotypic switching of vascular smooth muscle cells

Shushi Huang1,2, Wu Luo1,3, Gaojun Wu2, Qirui Shen1, Zaishou Zhuang3, Daona Yang3, Jinfu Qian1, Xiang Hu4, Yan Cai3, Nipon Chattipakorn5, Weijian Huang2, Guang Liang1,3,6
  • 1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
  • 2Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
  • 3Affiliated Cangnan Hospital, Wenzhou Medical University, Cangnan, Zhejiang 325000, China
  • 4Department of Endocrinology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
  • 5Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
  • 6School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China
* Equal contribution
Received: January 30, 2021Accepted: March 27, 2021Published: June 8, 2021
https://doi.org/10.18632/aging.202998

Copyright: © 2021 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: Recent studies have demonstrated a key role of vascular smooth muscle cell (VSMC) dysfunction in atherosclerosis. Cyclin-dependent kinases 9 (CDK9), a potential biomarker of atherosclerosis, was significantly increased in coronary artery disease patient serum and played an important role in inflammatory diseases. This study was to explore the pharmacological role of CDK9 inhibition in attenuating atherosclerosis.

Methods: A small-molecule CDK9 inhibitor, LDC000067, was utilized to treat the high fat diet (HFD)-fed ApoE-/- mice and human VSMCs.

Results: The results showed that inflammation and phenotypic switching of VSMCs were observed in HFD-induced atherosclerosis in ApoE-/- mice, which were accompanied with increased CDK9 in the serum and atherosclerotic lesions where it colocalized with VSMCs. LDC000067 treatment significantly suppressed HFD-induced inflammation, proliferation and phenotypic switching of VSMCs, resulting in reduced atherosclerosis in the ApoE-/- mice, while had no effect on plasma lipids. Further in vitro studies confirmed that LDC000067 and siRNA-mediated CDK9 knockdown reversed ox-LDL-induced inflammation and phenotypic switching of VSMCs from a contractile phenotype to a synthetic phenotype via inhibiting NF-κB signaling pathway in human VSMCs.

Conclusion: These results indicate that inhibition of CDK9 may be a novel therapeutic target for the prevention of atherosclerosis.