A high-salt diet promotes hypertrophic scarring through TRPC3-mediated mitochondrial Ca(2+) homeostasis dysfunction

Diet High in salt content have been associated with cardiovascular disease and chronic inflammation. We recently demonstrated that transient receptor potential canonical 3 (TRPC3) channels regulate myofibroblast transdifferentiation in hypertrophic scars. Here, we examined how high salt activation of TRPC3 participates in hypertrophic scarring during wound healing. In vitro, we confirmed that high salt increased the TRPC3 protein expression and the marker of myofibroblast alpha smooth muscle actin (α-SMA) in wild-type mice (WT) primary cultured dermal fibroblasts but not Trpc3(−/−) mice. Activation of TRPC3 by high salt elevated cytosolic Ca(2+) influx and mitochondrial Ca(2+) uptake in dermal fibroblasts in a TRPC3-dependent manner. High salt activation of TRPC3 enhanced mitochondrial respiratory dysfunction and excessive ROS production by inhibiting pyruvate dehydrogenase action, that activated ROS-triggered Ca(2+) influx and the Rho kinase/MLC pathway in WT mice but not Trpc3(−/−) mice. In vivo, a persistent high-salt diet promoted myofibroblast transdifferentiation and collagen deposition in a TRPC3-dependent manner. Therefore, this study demonstrates that high salt enhances myofibroblast transdifferentiation and promotes hypertrophic scar formation through enhanced mitochondrial Ca(2+) homeostasis, which activates the ROS-mediated pMLC/pMYPT1 pathway. TRPC3 deficiency antagonizes high salt diet-induced hypertrophic scarring. TRPC3 may be a novel target for hypertrophic scarring during wound healing.