气候变化领域集成服务门户(CCPortal): Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm

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DOI	10.1073/pnas.2107898118
	Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm
	Zhang C.; Zhao H.; Cai Y.; Xiong J.; Mohan A.; Lou D.; Shi H.; Zhang Y.; Long X.; Wang J.; Yan C.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:31
英文摘要	Abdominal aortic aneurysm (AAA) is characterized by aorta dilation due to wall degeneration, which mostly occurs in elderly males. Vascular aging is implicated in degenerative vascular pathologies, including AAA. Cyclic nucleotide phosphodiesterases, by hydrolyzing cyclic nucleotides, play critical roles in regulating vascular structure remodeling and function. Cyclic nucleotide phosphodiesterase 1C (PDE1C) expression is induced in dedifferentiated and aging vascular smooth muscle cells (SMCs), while little is known about the role of PDE1C in aneurysm. We observed that PDE1C was not expressed in normal aorta but highly induced in SMC-like cells in human and murine AAA. In mouse AAA models induced by Angiotensin II or periaortic elastase, PDE1C deficiency significantly decreased AAA incidence, aortic dilation, and elastin degradation, which supported a causative role of PDE1C in AAA development in vivo. Pharmacological inhibition of PDE1C also significantly suppressed preestablished AAA. We showed that PDE1C depletion antagonized SMC senescence in vitro and/or in vivo, as assessed by multiple senescence biomarkers, including senescenceassociated β-galactosidase activity, γ-H2AX foci number, and p21 protein level. Interestingly, the role of PDE1C in SMC senescence in vitro and in vivo was dependent on Sirtuin 1 (SIRT1). Mechanistic studies further showed that cAMP derived from PDE1C inhibition stimulated SIRT1 activation, likely through a direct interaction between cAMP and SIRT1, which leads to subsequent up-regulation of SIRT1 expression. Our findings provide evidence that PDE1C elevation links SMC senescence to AAA development in both experimental animal models and human AAA, suggesting therapeutical significance of PDE1C as a potential target against aortic aneurysms. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Abdominal aortic aneurysm; Phosphodiesterase; Senescence; Vascular smooth muscle cell
语种	英语
scopus关键词	beta galactosidase; cyclic AMP; cyclic nucleotide phosphodiesterase; cyclic nucleotide phosphodiesterase 1C; histone H2AX; protein p21; sirtuin 1; unclassified drug; angiotensin II; beta galactosidase; biological marker; CDKN1A protein, human; cyclic AMP; cyclic nucleotide phosphodiesterase 1; cyclin dependent kinase inhibitor 1A; gamma-H2AX protein, mouse; H2AX protein, human; histone; messenger RNA; PDE1C protein, human; Pde1C protein, mouse; SIRT1 protein, human; Sirt1 protein, mouse; sirtuin 1; abdominal aortic aneurysm; animal cell; animal experiment; animal model; Article; cell aging; cell dedifferentiation; controlled study; enzyme activity; human; human cell; in vitro study; in vivo study; male; mouse; nonhuman; protein expression; vascular smooth muscle cell; abdominal aortic aneurysm; animal; apolipoprotein E knockout mouse; enzymology; gene expression regulation; genetics; metabolism; physiology; upregulation; Angiotensin II; Animals; Aortic Aneurysm, Abdominal; beta-Galactosidase; Biomarkers; Cellular Senescence; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Cyclin-Dependent Kinase Inhibitor p21; Gene Expression Regulation, Enzymologic; Histones; Male; Mice; Mice, Knockout, ApoE; RNA, Messenger; Sirtuin 1; Up-Regulation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251101
作者单位	Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, United States; Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, United States; State Key Laboratory of Medical Molecular Biology, Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China; Department of Clinical and Translational Research, University of Rochester Medical Center, Rochester, NY 14642, United States; Department of Public Health Sciences, University of Rochester Medical Center, Rochester, NY 14642, United States; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, United States
推荐引用方式 GB/T 7714	Zhang C.,Zhao H.,Cai Y.,et al. Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm[J],2021,118(31).
APA	Zhang C..,Zhao H..,Cai Y..,Xiong J..,Mohan A..,...&Yan C..(2021).Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm.Proceedings of the National Academy of Sciences of the United States of America,118(31).
MLA	Zhang C.,et al."Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm".Proceedings of the National Academy of Sciences of the United States of America 118.31(2021).