Treatment of calcific arterial disease via enhancement of autophagy using GSK343.
Treatment of calcific arterial disease via enhancement of autophagy using GSK343.
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DOI：
10.1016/j.isci.2023.108360
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发表时间：
2023-11-17
期刊：
影响因子：
5.8
通讯作者：
Malhotra, Rajeev
中科院分区：
文献类型：
--
作者：
Cardenas, Christian L. Lino;Jiang, Wanlin;Kajuluri, Lova P.;Singh, Kuldeep;Ostrom, Katrina;Li, Rebecca;Cherbonneau, Francois;Boerboom, Sophie;Birchenough, Claire;Roh, Kangsan;Chou, Elizabeth L.;Shahrooz, Zarbafian;Nicholson, Christopher;Johnson, Adam L.;Lee, Sujin;Ichinose, Fumito;Bloch, Donald B.;Nigwekar, Sagar;Ellinor, Patrick T.;Musolino, Patricia;Lindsay, Mark E.;Dou, Zhixun;Miller, Clint L.;Malhotra, Rajeev
血管钙化是动脉粥样硬化性疾病的标志，是心血管事件的强预测因子和危险因素。越来越多的证据表明，自噬可能在早期动脉粥样硬化中起保护作用。自噬对VSMC介导的钙化的确切影响仍然未知。在这项研究中，我们利用多组学分析，研究受损的自噬在转录水平作为一个关键的驱动程序的VSMC钙化。我们的研究结果表明，受损的自噬是VSMC钙化的一个重要决定因素。我们观察到成骨环境影响VSMC的开放染色质状态，损害自噬起始基因的转录激活。体内实验涉及使用自发性大动脉（Mgp−/−）和小动脉（Abcc 6 −/−）钙化的小鼠模型进行的自噬的药理学和遗传激活。总之，这些数据推进了我们对血管钙化机制的理解，并为涉及VSMC表型转换的广泛心血管疾病提供了重要的见解。自噬起始受损是血管钙化的决定因素钙化的VSMCS中自噬基因处的染色质重排GSK 343的染色质松弛恢复自噬起始基因表达自噬的药理学或遗传学增强抑制血管钙化心血管医学;人类遗传学;分子生理学
Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp−/−) and small (Abcc6−/−) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch. Impaired autophagy initiation is a determinant of vascular calcification Chromatin rearrangement at autophagy genes in calcified VSMCS Chromatin relaxation by GSK343 restores autophagy initiation gene expression Pharmacologic or genetic enhancement of autophagy inhibits vascular calcification Cardiovascular medicine; Human Genetics; Molecular physiology
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影响因子：
23.9
作者：
Lin B;Srikanth P;Castle AC;Nigwekar S;Malhotra R;Galloway JL;Sykes DB;Rajagopal J
通讯作者：
Rajagopal J
影响因子：
20.1
作者：
Abdellatif, Mahmoud;Sedej, Simon;Kroemer, Guido
通讯作者：
Kroemer, Guido
影响因子：
13.6
作者：
Nigwekar, Sagar U.;Bloch, Donald B.;Malhotra, Rajeev
通讯作者：
Malhotra, Rajeev
影响因子：
82.9
作者：
Klarin, Derek;Lynch, Julie;Damrauer, Scott M.
通讯作者：
Damrauer, Scott M.
影响因子：
4.8
作者：
Byon, Chang Hyun;Javed, Amjad;Chen, Yabing
通讯作者：
Chen, Yabing