TRPA1 Promotes Cardiac Myofibroblast Transdifferentiation after Myocardial Infarction Injury via the Calcineurin-NFAT-DYRK1A Signaling Pathway

Abstract

Cardiac fibroblasts (CFs) are a critical cell population responsible for myocardial extracellular matrix homeostasis. After stimulation by myocardial infarction (MI), CFs transdifferentiate into cardiac myofibroblasts (CMFs) and play a fundamental role in the fibrotic healing response. Transient receptor potential ankyrin 1 (TRPA1) channels are cationic ion channels with a high fractional Ca2+ current, and they are known to influence cardiac function after MI injury; however, the molecular mechanisms regulating CMF transdifferentiation remain poorly understood. TRPA1 knockout mice, their wild-type littermates, and mice pretreated with the TRPA1 agonist cinnamaldehyde (CA) were subjected to MI injury and monitored for survival, cardiac function, and fibrotic remodeling. TRPA1 can drive myofibroblast transdifferentiation initiated 1 week after MI injury. In addition, we explored the underlying mechanisms via in vitro experiments through gene transfection alone or in combination with inhibitor treatment. TRPA1 overexpression fully activated CMF transformation, while CFs lacking TRPA1 were refractory to transforming growth factor β- (TGF-β-) induced transdifferentiation. TGF-β enhanced TRPA1 expression, which promoted the Ca2+-responsive activation of calcineurin (CaN). Moreover, dual-specificity tyrosine-regulated kinase-1a (DYRK1A) regulated CaN-mediated NFAT nuclear translocation and TRPA1-dependent transdifferentiation. These findings suggest a potential therapeutic role for TRPA1 in the regulation of CMF transdifferentiation in response to MI injury and indicate a comprehensive pathway driving CMF formation in conjunction with TGF-β, Ca2+ influx, CaN, NFATc3, and DYRK1A.