2. Academic Validation
  3. OTUD1 promotes isoprenaline- and myocardial infarction-induced heart failure by targeting PDE5A in cardiomyocytes

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

  • Biochim Biophys Acta Mol Basis Dis. 2024 Jan 5:167018. doi: 10.1016/j.bbadis.2024.167018.
Qinyan Wang 1,  Shiqi Liang 1,  Jinfu Qian 2,  Jiachen Xu 2,  Qingsong Zheng 3,  Mengyang Wang 4,  Xiaochen Guo 3,  Julian Min 3,  Gaojun Wu 2,  Zaishou Zhuang 3,  Wu Luo 5,  Guang Liang 6
Affiliations

Affiliations

  • 1 The Affiliated Cangnan Hospital and Chemical Biology Research Center, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; Department of Cardiology and Medical Research Center, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 2 Department of Cardiology and Medical Research Center, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 3 The Affiliated Cangnan Hospital and Chemical Biology Research Center, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
  • 4 Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, Jilin 132013, China.
  • 5 The Affiliated Cangnan Hospital and Chemical Biology Research Center, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; Department of Cardiology and Medical Research Center, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: wuluo@wmu.edu.cn.
  • 6 The Affiliated Cangnan Hospital and Chemical Biology Research Center, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; Department of Cardiology and Medical Research Center, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China. Electronic address: wzmcliangguang@163.com.
PMID: 38185350 DOI: 10.1016/j.bbadis.2024.167018
Abstract

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-PKG-SERCA2a 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.

Keywords

Heart failure; Isoprenaline; Myocardial infarction; OTUD1; PDE5A.

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