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  3. Terazosin attenuates abdominal aortic aneurysm formation by downregulating Peg3 expression to inhibit vascular smooth muscle cell apoptosis and senescence

Terazosin attenuates abdominal aortic aneurysm formation by downregulating Peg3 expression to inhibit vascular smooth muscle cell apoptosis and senescence

  • Eur J Pharmacol. 2024 Feb 7:968:176397. doi: 10.1016/j.ejphar.2024.176397.
Xiuxian Wei 1,  Yi Li 1,  Tao Jiang 1,  Pengcheng Luo 1,  Yue Dai 1,  Qian Wang 1,  Mulin Xu 2,  Jinhua Yan 1,  Yongjun Li 3,  Jingwen Gao 4,  Lei Liu 4,  Cuntai Zhang 1,  Yu Liu 5
Affiliations

Affiliations

  • 1 Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2 Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China.
  • 4 Department of Biochemistry and Molecular Biology School of Basic Medicine, Capital Medical University, Youanmen, Beijing, 100069, China.
  • 5 Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: liuyu2012@tjh.tjmu.edu.cn.
PMID: 38331337 DOI: 10.1016/j.ejphar.2024.176397
Abstract

Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells (VSMCs), degradation of extracellular matrix (ECM), inflammation, and oxidative stress. Despite the severity of AAA, effective drugs for treatment are scarce. At low doses, terazosin (TZ) exerts antiapoptotic and anti-inflammatory effects in several diseases, but its potential to protect against AAA remains unexplored. Herein, we investigated the effects of TZ in two AAA animal models: Angiotensin II (Ang II) infusion in Apoe-/- mice and calcium chloride application in C57BL/6J mice. Mice were orally administered with TZ (100 or 1000 μg/kg/day). The in vivo results indicated that low-dose TZ alleviated AAA formation in both models. Low-dose TZ significantly reduced aortic pulse wave velocity without exerting an apparent antihypertensive effect in the Ang II-induced AAA model. Paternally expressed gene 3 (Peg3) was identified via RNA Sequencing as a novel TZ target. PEG3 expression was significantly elevated in both mouse and human AAA tissues. TZ suppressed PEG3 expression and reduced the abundance of Matrix Metalloproteinases (MMP2/MMP9) in the tunica media. Functional experiments and molecular analyses revealed that TZ (10 nM) treatment and Peg3 knockdown effectively prevented Ang II-induced VSMC senescence and Apoptosis in vitro. Thus, Peg3, a novel target of TZ, mediates inflammation-induced VSMC Apoptosis and senescence. Low-dose TZ downregulates Peg3 expression to attenuate AAA formation and ECM degradation, suggesting a promising therapeutic strategy for AAA.

Keywords

Abdominal aortic aneurysm; Cell senescence; Paternally expressed gene 3; TZ; VSMC apoptosis.

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