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.

Angiotensin-II-Evoked Ca2+ Entry in Murine Cardiac Fibroblasts Does Not Depend on TRPC Channels

“…In primary human ventricular CFs methylglyoxal provokes a sustained increase in the intracellular Ca 2+ concentration that is largely reduced by treatment with HC030031, a selective TRPA1 antagonist or by TRPA1 knockdown using siRNA [104]. In CFs from TRPA1-deficient mice the transdifferentiation evoked by TGF-β is strongly reduced; in vivo, cardiac fibrosis is reduced in TRPA1-KO mice after myocardial infarction but is increased in WT mice treated with the TRPA1 agonist cinnamaldehyde [105]. However, it remains still unclear whether development of cardiac fibrosis in these experiments is mediated by TRPA1 channels present in CFs or other cell types.…”

Ca2+ Signaling in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases

“…In this review, we focus on summarizing the recent advances regarding the role of TRP channels in mediating Ca 2+ signaling in cardiac fibroblasts, and their potential roles in cardiac fibrosis and fibrosis-associated heart diseases [37,39,70,164,165] (Table 2). [197][198][199][200] 3.4. Ca 2+ Signaling Mediated by TRP Channels in Cardiac Fibroblasts and Fibrosis-Associated Heart Diseases…”

“…TRPA1 is expressed in cardiac myocytes [197,198] and fibroblasts [199]. Activation of TRPA1 elicits Ca 2+ influx in primary cultured human ventricular cardiac fibroblasts [73].…”

“…TRPA1 selective inhibitors HC-030031 (HC) and TCS-5861528 (TCS) ameliorate pressure-overload-induced cardiac hypertrophy by negatively regulating Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and calcineurin signaling pathways [200]. The knockout TRPA1 increases survival rate, reduces fibrosis, and enhances heart performance after myocardial infarction [199]. Moreover, in primary cultured cardiac fibroblasts, an overexpression of TRPA1 potentiates, whereas a knockdown TRPA1 attenuates, TGF-β1-induced fibroblast differentiation.…”

Small Molecule Inhibitors of DYRK1A Identified by Computational and Experimental Approaches

“…Additionally, they showed hydrogen bond interactions with Lys188 ( Figure 3 ). These residues are known to play important roles in DYRK1A kinase activity and in the binding of DYRK1A inhibitors [ 14 , 44 ]. We calculated TWN–ligand shape similarity for the compounds and obtained reasonable similarities of 36% and 44% for AZD1080 and SB-415286, respectively.…”