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

Abstract

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 involved in myocardial fibrosis. However, little is known about the role of nitrated CREB in MI-induced myocardial fibrosis. Meanwhile, downstream transcription genes of 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 (i) the level of nitrative stress was elevated and nitrated CREB was higher in myocardium after MI. Tyr182, 307 and 336 were the nitration sites of CREB; (ii) with the administration of FeTMPyP (scavenger of ONOO-), CREB phosphorylation, nuclear translocation, binding activity to TORC2 (transducers of regulated CREB-2) were attenuated; (iii) the expressions of ECM proteins were up-regulated and down-regulated in accordance with the expression alteration of CREB both in vitro and in vivo; (iv) CREB accelerated transcription of col1a2 and cxcl12 after MI directly. With the administration of FeTMPyP, ECM proteins expressions were attenuated, meanwhile, the mRNA level 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 transcript col1a2 and cxcl12 directly. These data indicated that nitrated CREB might be a potential therapeutic target against MI-induced myocardial fibrosis.