zDHHC9 Regulates Cardiomyocyte Rab3a Activity and Atrial Natriuretic Peptide Secretion Through Palmitoylation of Rab3gap1.
zDHHC9 Regulates Cardiomyocyte Rab3a Activity and Atrial Natriuretic Peptide Secretion Through Palmitoylation of Rab3gap1.
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DOI：
10.1016/j.jacbts.2022.11.003
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发表时间：
2023-05
影响因子：
9.7
通讯作者：
Brody, Matthew J.
中科院分区：
文献类型：
--
作者：
Essandoh, Kobina;Subramani, Arasakumar;Ferro, Olivia A.;Teuber, James P.;Koripella, Sribharat;Brody, Matthew J.
zDHHC 9通过Rab 3gap 1的棕榈酰化调节心肌细胞Rab 3a活性和ANP释放。Rab 3a在体内定位于心房颗粒，心肌细胞中zDHHC 9的转基因过表达导致心房ANP、Rab 3a和Rab 3gap 1水平、心房颗粒形态和循环ANP水平失调。zDHHC 9、Rab 3gap 1和Rab 3a在ANP分泌的分子调节中的作用为心力衰竭和心血管疾病中利钠肽信号传导的治疗增强提供了新的靶点。应激心脏产生和释放利钠肽通过促进血管舒张、利钠和利尿来降低心脏工作负荷，这在最近开发的新型心力衰竭药物治疗中已被利用，但调节心肌细胞胞吐和利钠肽释放的机制仍不明确。我们发现，高尔基体S-酰基转移酶zDHHC 9棕榈酰化Rab 3gap 1，导致其从Rab 3a的空间分离，Rab 3a-GTP水平的升高，Rab 3a阳性外周囊泡的形成，以及限制心房利钠肽释放的胞吐作用的损害。这种新的途径可能被用于靶向利钠肽信号转导治疗心力衰竭。
zDHHC9 regulates cardiomyocyte Rab3a activity and ANP release through palmitoylation of Rab3gap1. Rab3a localizes to atrial granules in vivo, and transgenic overexpression of zDHHC9 in cardiomyocytes results in dysregulated atrial ANP, Rab3a, and Rab3gap1 levels, atrial granule morphology, and circulating ANP levels. Roles identified for zDHHC9, Rab3gap1, and Rab3a in molecular regulation of ANP secretion provide novel targets for therapeutic enhancement of natriuretic peptide signaling in heart failure and cardiovascular disease. Production and release of natriuretic peptides by the stressed heart reduce cardiac workload by promoting vasodilation, natriuresis, and diuresis, which has been leveraged in the recent development of novel heart-failure pharmacotherapies, yet the mechanisms regulating cardiomyocyte exocytosis and natriuretic peptide release remain ill defined. We found that the Golgi S-acyltransferase zDHHC9 palmitoylates Rab3gap1 resulting in its spatial segregation from Rab3a, elevation of Rab3a-GTP levels, formation of Rab3a-positive peripheral vesicles, and impairment of exocytosis that limits atrial natriuretic peptide release. This novel pathway potentially can be exploited for targeting natriuretic peptide signaling in the treatment of heart failure.
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影响因子：
20.1
作者：
Ackers-Johnson M;Li PY;Holmes AP;O'Brien SM;Pavlovic D;Foo RS
通讯作者：
Foo RS
影响因子：
120.7
作者：
Chen, Horng H.;Anstrom, Kevin J.;Givertz, Michael M.;Stevenson, Lynne W.;Semigran, Marc J.;Goldsmith, Steven R.;Bart, Bradley A.;Bull, David A.;Stehlik, Josef;LeWinter, Martin M.;Konstam, Marvin A.;Huggins, Gordon S.;Rouleau, Jean L.;O'Meara, Eileen;Tang, W. H. Wilson;Starling, Randall C.;Butler, Javed;Deswal, Anita;Felker, G. Michael;O'Connor, Christopher M.;Bonita, Raphael E.;Margulies, Kenneth B.;Cappola, Thomas P.;Ofili, Elizabeth O.;Mann, Douglas L.;Davila-Roman, Victor G.;McNulty, Steven E.;Borlaug, Barry A.;Velazquez, Eric J.;Lee, Kerry L.;Shah, Monica R.;Hernandez, Adrian F.;Braunwald, Eugene;Redfield, Margaret M.
通讯作者：
Redfield, Margaret M.
影响因子：
4.6
作者：
Collins MO;Woodley KT;Choudhary JS
通讯作者：
Choudhary JS
影响因子：
11.8
作者：
Ernst AM;Syed SA;Zaki O;Bottanelli F;Zheng H;Hacke M;Xi Z;Rivera-Molina F;Graham M;Rebane AA;Björkholm P;Baddeley D;Toomre D;Pincet F;Rothman JE
通讯作者：
Rothman JE
DOI：
10.1161/hypertensionaha.121.17159
发表时间：
2021-12
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Chen HH;Wan SH;Iyer SR;Cannone V;Sangaralingham SJ;Nuetel J;Burnett JC Jr
通讯作者：
Burnett JC Jr