Nitration of cAMP-Response Element Binding Protein Participates in Myocardial Infarction-Induced Myocardial Fibrosis via Accelerating Transcription of Col1a2 and Cxcl12

Aims: Myocardial fibrosis after myocardial infarction (MI) leads to heart failure. Nitration of protein can alter its function. cAMP-response element binding protein (CREB) is a key transcription factor involved in fibrosis. However, little is known about the role of nitrated CREB in MI-induced myocardial fibrosis. Meanwhile, downstream genes of transcription factor CREB in myocardial fibrosis have not been identified. This study aims to verify the hypothesis that nitrated CREB promotes MI-induced myocardial fibrosis via regulating the transcription of Col1a2 and Cxcl12.Results: Our study showed that (1) the level of nitrative stress was elevated and nitrated CREB was higher in the myocardium after MI. Tyr182, 307, and 336 were the nitration sites of CREB; (2) with the administration of peroxynitrite (ONOO-) scavengers, CREB phosphorylation, nuclear translocation, and binding activity to TORC2 (transducers of regulated CREB-2) were attenuated; (3) the expressions of extracellular matrix (ECM) proteins were upregulated and downregulated in accordance with the expression alteration of CREB both in vitro and in vivo; (4) CREB accelerated transcription of Col1a2 and Cxcl12 after MI directly. With the administration of ONOO- scavengers, ECM protein expressions were attenuated; meanwhile, the messenger RNA (mRNA) levels of Col1a2 and Cxcl12 were alleviated as well.Innovation and Conclusion: Nitration of transcription factor CREB participates in MI-induced myocardial fibrosis through enhancing its phosphorylation, nuclear translocation, and binding activity to TORCs, among which CREB transcripts Col1a2 and Cxcl12 directly. These data indicated that nitrated CREB might be a potential therapeutic target against MI-induced myocardial fibrosis.

Automated summary

The study aims to verify the role of nitrated cAMP-response element binding protein (CREB) in myocardial fibrosis after myocardial infarction (MI) and identify its downstream genes. It was found that nitrated CREB promoted MI-induced myocardial fibrosis by enhancing its phosphorylation, nuclear translocation, and binding activity to TORCs. Additionally, CREB directly accelerated the transcription of Col1a2 and Cxcl12 after MI.