Valtrate attenuates arrhythmia after myocardial ischemia-reperfusion via inducing N-linked glycosylation modification of LTβR to suppress TNFSF14-induced reduction of Cx43

Abstract

Abstract Background Myocardial ischemia-reperfusion (MIR)-induced arrhythmia remains a major cause of death in cardiovascular patients. The reduction of Cx43 has been known as a major inducer of arrhythmias after MIR, but the reason for the reduction of Cx43 remain largely unknown. This study aimed to find the key mechanism underlying the reduction of Cx43 after MIR and to screen out a herbal extract to attenuate arrhythmia after MIR. Methods The differential expressed genes in peripheral blood macrophages after MIR was analyzed using the data from several GEO datasets, followed by the identification in the peripheral blood macrophages and the serum of patients with myocardial infarction. TNFSF14 was not only increased but also associated to the injury after MIR. The toxic effects of TNFSF14 on cardiomyocytes was investigated in vitro. Valtrate was screened out from several herbal extracts. Its protection against TNFSF14-induced injury was evaluated in cardiomyocytes and animal models with MIR. Results Recombinant TNFSF14 protein not only suppressed cardiomyocytes’ viability, but also decreased Cx43 by stimulating the receptor LTβR. LTβR induces the competitive binding of MAX to MGA rather than the transcriptional factor c-Myc, thereby suppressing c-Myc-mediated transcription of Cx43. Valtrate promoted the N-linked glycosylation modification of LTβR, which reversed TNFSF14-induced reduction of Cx43 and attenuated arrhythmia after MIR. Conclusion Valtrate suppresses TNFSF14-induced reduction of Cx43 thereby attenuating arrhythmia after MIR.