TRPV4-driven Regulation of miR-146a Expression in Macrophages and in a Mouse Model of Atherosclerosis

Abstract

MicroRNAs (miRs) are small, non-coding RNAs that have emerged as powerful regulators of gene expression. Emerging evidence suggests that miR-146a orchestrates anti-inflammatory/fibrotic processes in numerous cell types. Trpv4 (Transient Receptor Potential subfamily V member 4), a mechanosensitive, calcium-permeant channel/receptor, is expressed in numerous cell types including macrophages. Published work by our group and others show that Trpv4 is activated by a range of soluble and physical stimuli including matrix stiffness and cytokines. In mice, Trpv4 deficiency is associated with altered pressure responses, foreign body response, fibrosis, and inflammation. Previous work by our group and others suggest a pro-inflammatory/atherogenic role for Trpv4. Herein, we tested the hypothesis that Trpv4 regulates the expression of microRNA-146a in macrophages and in a mouse model of atherosclerosis. Our research found a 38% drop in miR-146a expression in macrophages treated with lipopolysaccharide (LPS) on a stiffer polyacrylamide hydrogel compared to a softer one as determined by RNAseq analysis, signifying miR-146a's sensitivity to mechanical factors. Trpv4's presence suppresses the LPS-induced increase of miR-146a in macrophages based on time and dosage. Trpv4 also plays a role in the suppression of miR-146a due to matrix stiffness. Notably, in mice, Trpv4 reduces the increase of macrophage miR-146a caused by a high-fat diet in aortic root regions. Given that matrix stiffening is common in atherosclerosis, this indicates a link between stiffness, Trpv4, and miR-146a. On the mechanism side, Trpv4 affects miR-146a expression not through its promoter methylation or activation of MAPKs, Stat1, AKT, and NFκB. Trpv4 residues 100 to 130 are required for suppression of LPS-induced upregulation of miR-146a. To sum up, Trpv4 appears to inhibit macrophage miR-146a expression through pathways that are distinct from those involving MAKPs/Stat1/AKT or NFκB. Understanding this mechanism could pave the way for new treatments targeting miR-146a to counter inflammatory diseases. Source of research support: NIH (R01 AI172086) grant to Shaik O. Rahaman. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.