- 作者: Jie Ju, Xin-Min Li, Xue-Mei Zhao, Fu-Hai Li, Shao-Cong Wang, Kai Wang, Rui-Feng Li, Lu-Yu Zhou, Lin Liang, Yin Wang, Yu-Hui Zhang & Kun Wang
- 作者服務機構: 1.Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266021, China 2.Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China 3.Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China 4.State Key Laboratory of Cardiovascular Disease, Heart Failure Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100037, China
- 中文摘要:
- 英文摘要:
Background Emerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death
after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has
been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key
circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function.
Methods We performed circRNA sequencing to explore circRNAs diferentially expressed after myocardial I/R. We
used quantitative polymerase chain reactions to determine the circRNA expression in diferent tissues and detect the
circRNA subcellular localization in the cardiomyocyte. Gain- and loss-of-function experiments were aimed to examine
the function of circRNAs in cardiomyocyte ferroptosis and cardiac tissue damage after myocardial I/R. RNA pull-down
was applied to explore proteins interacting with circRNA.
Results Here, we identifed a ferroptosis-associated circRNA (FEACR) that has an underlying regulatory role in car‑
diomyocyte ferroptosis. FEACR overexpression suppressed I/R-induced myocardial infarction and ameliorated cardiac
function. FEACR inhibition induces ferroptosis in cardiomyocytes and FEACR overexpression inhibits hypoxia and
reoxygenation-induced ferroptosis. Mechanistically, FEACR directly bound to nicotinamide phosphoribosyltransferase
(NAMPT) and enhanced the protein stability of NAMPT, which increased NAMPT-dependent Sirtuin1 (Sirt1) expres‑
sion, which promoted the transcriptional activity of forkhead box protein O1 (FOXO1) by reducing FOXO1 acetylation
levels. FOXO1 further upregulated the transcription of ferritin heavy chain 1 (Fth1), a ferroptosis suppressor, which
resulted in the inhibition of cardiomyocyte ferroptosis.
Conclusions Our fnding reveals that the circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 signaling axis partici‑
pates in the regulation of cardiomyocyte ferroptosis and protects the heart function against I/R injury. Thus, FEACR
and its downstream factors could be novel targets for alleviating ferroptosis-related myocardial injury in ischemic
heart diseases. - 中文關鍵字:
- 英文關鍵字: circRNA, FEACR, Cardiomyocyte ferroptosis, NAMPT