CircHIPK2 recruits SRSF1 to increase TXNIP mRNA stability and promotes autophagy-dependent ferroptosis and apoptosis in myocardial ischemia-reperfusion injury.
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引用次数: 0
Abstract
Background: Myocardial ischemia/reperfusion injury (MIRI) secondary to acute myocardial infarction (AMI) can lead to cardiomyocyte death and impaired cardiac function. Studies have confirmed that circular RNAs (circRNAs) play an important role in MIRI. In this study, the role and mechanism of circHIPK2 in MIRI were evaluated.
Methods: Human cardiac myocytes (HCM) were cultured under Hypoxia/Reoxygenation (H/R) condition to establish a MIRI model in vitro. Expression of circHIPK2, SRSF1 and TXNIP was assessed using RT-qPCR. Protein levels of autophagy markers (LC3II/LC3I, Beclin1, p62) and ferroptosis markers (GPX4, FTH1, ACSL4) were detected by Western blot. Cell viability and apoptosis were assessed by CCK-8 and flow cytometry. Levels of oxidative stress markers (MDA, SOD) and inflammatory factors (IL-6, IL-1β, TNF-α) were tested by ELISA assay. Iron concentration was measured with an iron detection kit. Location of circHIPK2 in cells was detected by RNA-nucleosome separation assay. RIP and ChIP assays verified the relationship between circHIPK2, SRSF1 and TXNIP. TXNIP mRNA stability was dertermined by actinomycin D. Infarct area was examined by TTC staining in myocardial ischemia/reperfusion (I/R) mouse model. HE staining evaluated myocardial injury.
Results: CircHIPK2 was increased in H/R-induced HCM cells. CircHIPK2 downregulation suppressed oxidative stress, inflammatory factors and autophagy-dependent ferroptosis in HCM cells induced by H/R. Additionally circHIPK2 recruited SRSF1 to target TXNIP and stabilized TXNIP mRNA expression. We further demonstrated that TXNIP upregulation overturned the therapeutic effects of circHIPK2 silencing on H/R model cells. In vivo, downregulation of circHIPK2 improved myocardial dysfunction caused by I/R.
Conclusion: Our results demonstrate that circHIPK2 contributes to MIRI through inducing oxidative stress and autophagy-dependent ferroptosis via SRSF1/TXNIP axis, offering new insights into MIRI treatment.
期刊介绍：
Journal of Cardiothoracic Surgery is an open access journal that encompasses all aspects of research in the field of Cardiology, and Cardiothoracic and Vascular Surgery. The journal publishes original scientific research documenting clinical and experimental advances in cardiac, vascular and thoracic surgery, and related fields.
Topics of interest include surgical techniques, survival rates, surgical complications and their outcomes; along with basic sciences, pediatric conditions, transplantations and clinical trials.
Journal of Cardiothoracic Surgery is of interest to cardiothoracic and vascular surgeons, cardiothoracic anaesthesiologists, cardiologists, chest physicians, and allied health professionals.
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