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

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 (similar to 7kDa) 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. Heart disease: circular RNA linked to heart cell death The production of a circular RNA molecule called circCDYL2 and the protein it codes for is significantly increased in rat heart muscle cells following loss of blood supply after a heart attack, suggesting new targets for treatment. The circCDYL2 RNA carries the genetic instructions to make a small protein called Cdyl2-60aa. Shaoliang Chen and colleagues at Nanjing Medical University in China detected the increased circCDYL2 in cells from rats with heart failure, and also in cultured rat heart muscle cells experimentally deprived of oxygen and glucose to simulate heart failure. Their research revealed details of the molecular mechanisms allowing Cdyl2-60aa to be produced and then to accelerate the death of heart muscle cells. If applicable to humans, the findings suggest new treatment possibilities by targeting the activity or production of the Cdyl2-60aa protein.

Automated summary

A circular RNA molecule, circCDYL2, and its protein product, Cdyl2-60aa, are significantly increased in rat heart muscle cells after myocardial infarction, promoting the death of heart muscle cells. Cdyl2-60aa enhances the stability of apoptotic protease activating factor-1 (APAF1) by blocking its ubiquitination by heat shock protein 70 (HSP70).