2. Academic Validation
  3. Cdyl2-60aa encoded by CircCDYL2 accelerates cardiomyocyte death by blocking APAF1 ubiquitination in rats

Cdyl2-60aa encoded by CircCDYL2 accelerates cardiomyocyte death by blocking APAF1 ubiquitination in rats

  • Exp Mol Med. 2023 Apr 3. doi: 10.1038/s12276-023-00983-5.
Yunfei Deng # 1,  Xiaochen Zeng # 2,  Yifei Lv 1,  Zhiyuan Qian 1,  Peijie Guo 3,  Yi Liu 4,  Shaoliang Chen 5
Affiliations

Affiliations

  • 1 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 2 Department of Clinical Laboratory, Children's Hospital of Nanjing Medical University, Nanjing, China.
  • 3 Department of Functional Examination, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 4 Department of Cell Biology, University of California, Davis, CA, USA.
  • 5 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 37009805 DOI: 10.1038/s12276-023-00983-5
Abstract

The loss of cardiomyocytes (CMs) after myocardial infarction (MI) is widely acknowledged to initiate the development of heart failure (HF). Herein, we found that circCDYL2 (583 nt) derived from chromodomain Y-like 2 (Cdyl2) is significantly upregulated in vitro (oxygen-glucose deprivation (OGD)-treated CMs) and in vivo (failing heart post-MI) and can be translated into a polypeptide termed Cdyl2-60aa (~7 kDa) in the presence of internal ribosomal entry sites (IRES). Downregulation of circCDYL2 significantly decreased the loss of OGD-treated CMs or the infarcted area of the heart post-MI. Additionally, elevated circCDYL2 significantly accelerated CM Apoptosis via Cdyl2-60aa. We then discovered that Cdyl2-60aa could stabilize protein apoptotic protease activating factor-1 (APAF1) and promote CM apoptosis; heat shock protein 70 (HSP70) mediated APAF1 degradation in CMs by ubiquitinating APAF1, which Cdyl2-60aa could competitively block. In conclusion, our work substantiated the claim that circCDYL2 could promote CM Apoptosis via Cdyl2-60aa, which enhanced APAF1 stability by blocking its ubiquitination by HSP70, suggesting that it is a therapeutic target for HF post-MI in rats.

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