OTUD1 promotes isoprenaline- and myocardial infarction-induced heart failure by targeting PDE5A in cardiomyocytes

被引:7
|
作者
Wang, Qinyan [1 ,2 ,3 ,4 ]
Liang, Shiqi [1 ,2 ,3 ,4 ]
Qian, Jinfu [3 ,4 ]
Xu, Jiachen [3 ,4 ]
Zheng, Qingsong [1 ,2 ]
Wang, Mengyang [6 ]
Guo, Xiaochen [1 ,2 ]
Min, Julian [1 ,2 ]
Wu, Gaojun [3 ,4 ]
Zhuang, Zaishou [1 ,2 ]
Luo, Wu [1 ,2 ,3 ,4 ]
Liang, Guang [1 ,2 ,3 ,4 ,5 ]
机构
[1] Wenzhou Med Univ, Affiliated Cangnan Hosp, Wenzhou 325000, Zhejiang, Peoples R China
[2] Wenzhou Med Univ, Chem Biol Res Ctr, Wenzhou 325000, Zhejiang, Peoples R China
[3] Wenzhou Med Univ, Affiliated Hosp 1, Dept Cardiol, Wenzhou 325035, Zhejiang, Peoples R China
[4] Wenzhou Med Univ, Affiliated Hosp 1, Med Res Ctr, Wenzhou 325035, Zhejiang, Peoples R China
[5] Hangzhou Med Coll, Sch Pharmaceut Sci, Hangzhou 311399, Zhejiang, Peoples R China
[6] Beihua Univ, Coll Pharm, Dept Pharmacol, Jilin 132013, Jilin, Peoples R China
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2024年 / 1870卷 / 03期
基金
中国国家自然科学基金;
关键词
OTUD1; Isoprenaline; Myocardial infarction; PDE5A; Heart failure; CYCLIC-GMP; PHOSPHODIESTERASES; TRENDS;
D O I
10.1016/j.bbadis.2024.167018
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Heart failure represents a major cause of death worldwide. Recent research has emphasized the potential role of protein ubiquitination/deubiquitination protein modification in cardiac pathology. Here, we investigate the role of the ovarian tumor deubiquitinase 1 (OTUD1) in isoprenaline (ISO)- and myocardial infarction (MI) -induced heart failure and its molecular mechanism. OTUD1 protein levels were raised markedly in murine cardiomyocytes after MI and ISO treatment. OTUD1 deficiency attenuated myocardial hypertrophy and cardiac dysfunction induced by ISO infusion or MI operation. In vitro, OTUD1 knockdown in neonatal rat ventricular myocytes (NRVMs) attenuated ISO -induced injuries, while OTUD1 overexpression aggravated the pathological changes. Mechanistically, LC-MS/MS and Co-IP studies showed that OTUD1 bound directly to the GAF1 and PDEase domains of PDE5A. OTUD1 was found to reverse K48 ubiquitin chain in PDE5A through cysteine at position 320 of OTUD1, preventing its proteasomal degradation. PDE5A could inactivates the cGMP-PKGSERCA2a signaling axis which dysregulate the calcium handling in cardiomyocytes, and leading to the cardiomyocyte injuries. In conclusion, OTUD1 promotes heart failure by deubiquitinating and stabilizing PDE5A in cardiomyocytes. These findings have identified PDE5A as a new target of OTUD1 and emphasize the potential of OTUD1 as a target for treating heart failure.
引用
收藏
页数:13
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