NKRF in Cardiac Fibroblasts Protects against Cardiac Remodeling Post‐Myocardial Infarction via Human Antigen R

• Published in: Advanced science Vol. 10; no. 30; p. e2303283
• Main Authors: Guo, Chenghu, Ji, Wei, Yang, Wei, Deng, Qiming, Zheng, Tengfei, Wang, Zunzhe, Sui, Wenhai, Zhai, Chungang, Yu, Fangpu, Xi, Bo, Yu, Xiao, Xu, Feng, Zhang, Qunye, Zhang, Wencheng, Kong, Jing, Zhang, Meng, Zhang, Cheng
• Format: Journal Article
• Language: English
• Published: Weinheim John Wiley & Sons, Inc 01.10.2023; John Wiley and Sons Inc; Wiley
• Subjects: cardiac fibroblasts; Cardiac function; Collagen; Coronary vessels; Disease; Fibroblasts; Genes; Heart attacks; Heart failure; Homeostasis; human antigen R; Hypertension; Inflammation; Ischemia; myocardial infarction; NF‐κB‐repressing factor; Proteins; RNA polymerase; transcriptional and post‐transcriptional regulation; Tuberculosis
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202303283

Myocardial infarction (MI) remains the leading cause of death worldwide. Cardiac fibroblasts (CFs) are abundant in the heart and are responsible for cardiac repair post-MI. NF-κB-repressing factor (NKRF) plays a significant role in the transcriptional inhibition of various specific genes. However, the NKRF action mechanism in CFs remains unclear in cardiac repair post-MI. This study investigates the NKRF mechanism in cardiac remodeling and dysfunction post-MI by establishing a CF-specific NKRF-knockout (NKRF-CKO) mouse model. NKRF expression is downregulated in CFs in response to pathological cardiac remodeling in vivo and TNF-α in vitro. NKRF-CKO mice demonstrate worse cardiac function and survival and increased infarct size, heart weight, and MMP2 and MMP9 expression post-MI compared with littermates. NKRF inhibits CF migration and invasion in vitro by downregulating MMP2 and MMP9 expression. Mechanistically, NKRF inhibits human antigen R (HuR) transcription by binding to the classical negative regulatory element within the HuR promoter via an NF-κB-dependent mechanism. This decreases HuR-targeted Mmp2 and Mmp9 mRNA stability. This study suggests that NKRF is a therapeutic target for pathological cardiac remodeling.