Angiotensin II Promotes the Phenotypic Transition of c-Kit+ Cardiac Interstitial Cells to Myofibroblasts Through Collagen Receptor Discoidin Domain Receptor 2.

Angiotensin II (Ang II), a potent profibrotic stimulus, exhibits pleiotropic effects on cardiac cells. The fate of c-Kit+ cells in an Ang II-elevated injured myocardium remains poorly defined. This study investigated, in vitro, the effect of Ang II on the phenotype of non-hematopoietic non-endothelial c-Kit+ cardiac interstitial cells (CICs), expressing OCT4. Our findings demonstrate that Ang II directly drives the phenotypic transition of c-Kit+ CICs into α-SMA-expressing myofibroblasts, accompanied by significant upregulation of prominent myofibroblast markers, SM22-α, collagen type IA, and its crosslinking enzyme, lysyl oxidase. Through targeted silencing experiments, we confirmed that Ang II-mediated phenotypic transition occurs via activation of the ERK1/2 MAPK pathway, triggered by collagen receptor Discoidin domain receptor 2 (DDR2), and involves the transcription factor, serum response factor (SRF). These results indicate that c-Kit+ CICs are susceptible to myofibroblast transition in the infarcted myocardium, and may serve as an additional source of myofibroblasts contributing to repair and remodeling alongside resident fibroblasts. Additionally, we observed that overexpression of c-Kit attenuated Ang II-induced α-SMA upregulation by downregulating DDR2-ERK1/2-SRF signaling in c-Kit+ CICs, highlighting the pivotal role of c-Kit expression levels in regulating cell fate. Furthermore, overexpression of c-Kit in Ang II-treated cardiac fibroblasts significantly reduced the expression of myofibroblast proteins, α-SMA, SM22-α, periostin, collagen type IA, collagen receptor DDR2, and lysyl oxidase, and resembled c-Kit+ CICs in morphology. Collectively, these results suggest that c-Kit expression in myofibroblasts may potentially mitigate the adverse effects of cardiac fibrosis and promote favorable remodeling in the long term.