MKRN1 Alleviates Intermittent Hypoxia-Induced Myocardial Apoptosis Through Regulating P21 Ubiquitylation

Background: With the increase of obesity,the incidence of obstructive sleep apnea hypopnoea syndrome(OSAHS)is increasing year by year,and OSAHS has become an independent risk factor for various cardiovascular diseases.Chronic intermittent hypoxia(IH)is the main pathological feature of OSAHS.Cardiomyocyte apoptosis induced by IH is the key pathophysiological process leading to poor prognosis in patients with OSAHS.Hence,understanding the molecular mechanism of cardiomyocyte apoptosis induced by intermittent hypoxia is of important clinical significance to reduce cardiovascular damage caused by OSAHS and improve the prognosis of OSAHS patients.Many apoptosis regulatory molecules can regulate apoptosis and affect organ function in OSAHS.IH can increase myocardial apoptosis by inducing abnormal expression of apoptosis regulatory factors.However,it is not clear which apoptosis regulatory molecule that is abnormally expressed leads to the increase of myocardial apoptosis and its mechanism.Objective: To investigate the role of apoptosis regulatory molecule which is abnormally expressed in IH-induced myocardial apoptosis and its possible molecular mechanism.Methods: 1.The differentially expressed apoptotic regulatory molecules in IH myocardium were screened by bioinformatics analysis,and the IH model of SD rats,rat cardiomyocyte H9C2 and human cardiomyocyte AC16 were established to verify the differential expression of this molecule(Part ?).2.Cell model was used to study the role of MKRN1,an abnormally expressed apoptosis regulatory molecule in IH myocardium,in improving myocardial apoptosis and ROS production induced by IH and the p21 signal mechanism(Part?).3.The molecular mechanism of MKRN1 regulating p21 protein expression was studied by co-immunoprecipitation and ubiquitin experiments(Part?).Results: 1.Bioinformatics showed that MKRN1 is an apoptosis regulatory molecule differentially expressed in IH myocardium.Animal and cell experiments showed that the expression of MKRN1 was down-regulated in IH myocardial model.2.Cell experiments show that MKRN1 inhibits the excessive production of ROS through p21 pathway and plays a role in reducing IH-induced myocardial apoptosis.3.Cell experiments showed that MKRN1 negatively regulated p21 by promoting ubiquitination and proteasome degradation of p21.Conclusion: 1.The method of bioinformatics screening combined with experimental verification is a feasible method to find the potential therapeutic targets for myocardial injury caused by IH.2.MKRN1 inhibits p21 pathway by enhancing p21 ubiquitination,reducing the stability of p21 protein,thus resists the excessive production of ROS,reduces cardiomyocyte apoptosis and alleviates myocardial injury caused by IH.