Valtrate suppresses TNFSF14-mediated arrhythmia after myocardial ischemia-reperfusion via inducing N-linked glycosylation of LTβR to regulate MGA/MAX/c-Myc/Cx43

Myocardial ischemia-reperfusion (MIR)-induced arrhythmia remains a major cause of death in patients with cardiovascular diseases. 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. The differential expressed genes in peripheral blood mononuclear cell (PBMC) after MIR was analyzed using the data from several GEO datasets, followed by the identification in the PBMC and the serum of patients with myocardial infarction. Tumour necrosis factor superfamily protein 14 (TNFSF14) was increased in the the PBMC and the serum of patients, which might be 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. Recombinant TNFSF14 protein not only suppressed the viability of cardiomyocytes, 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. In all, Valtrate suppresses TNFSF14-induced reduction of Cx43 thereby attenuating arrhythmia after MIR.