HuR inhibition reduces post‐ischemic cardiac remodeling by dampening myocyte‐dependent inflammatory gene expression and the innate immune response

作者：Samuel Slone, Sarah Anthony, Lisa C. Green, Sharon Parkins, Pooja Acharya, Daniel A. Kasprovic, Kelsi Reynolds, Robert M. Jaggers, Michelle L. Nieman, Perwez Alam, Xiaoqing Wu, Sudeshna Roy, Jeffrey Aubé, Liang Xu, Zihai Li, John N. Lorenz, A. Phillip Owens, Onur Kanisicak, Michael Tranter · 发表于：The FASEB Journal · 年份：2025 · DOI：10.1096/fj.202400532rrr · 被引用次数：6 · 研究领域：RNA Research and Splicing、Cardiac Fibrosis and Remodeling、Signaling Pathways in Disease

The RNA-binding protein human antigen R (HuR) has been shown to reduce cardiac remodeling following both myocardial infarction and cardiac pressure overload, but the full extent of the HuR-dependent mechanisms within cells of the myocardium has yet to be elucidated. Wild-type mice were subjected to 30 min of cardiac ischemia (via LAD occlusion) and treated with a novel small molecule inhibitor of HuR at the time of reperfusion, followed by direct in vivo assessment of cardiac structure and function. Direct assessment of HuR-dependent mechanisms was done in vitro using neonatal rat ventricular myocytes (NRVMs) and bone marrow-derived macrophages (BMDMs). HuR activity is increased within 2 h after ischemia/reperfusion (I/R) and is necessary for early post-I/R inflammatory gene expression in the myocardium. Despite an early reduction in inflammatory gene expression, HuR inhibition has no effect on initial infarct size at 24 h post-I/R. However, pathological remodeling is reduced with preserved cardiac function at 2 weeks post-I/R upon HuR inhibition. RNA sequencing analysis of gene expression in NRVMs treated with LPS to model damage-associated molecular pattern (DAMP)-mediated activation of toll-like receptors (TLRs) demonstrates a HuR-dependent regulation of pro-inflammatory chemokine and cytokine gene expression in cardiomyocytes. Importantly, we show that conditioned media transfer from NRVMs pre-treated with HuR inhibitor loses the ability to induce inflammatory gene expres...