Inhibition of TRPC1 prevents cardiac hypertrophy via NF-κB signaling pathway in human pluripotent stem cell-derived cardiomyocytes.

Cardiac hypertrophy is an adaptive response against increased workload featuring by an increase in left ventricular mass and a thickening left ventricle wall. Here, we showed the expression of transient receptor potential canonical 1 (TRPC1) is higher in hearts of patients with hypertrophic cardiomyopathy (HCM) or heart failure (HF) than that of normal hearts. To better understand the mechanisms of TRPC1 in regulating cellular hypertrophy of human-based cardiomyocytes, we generated human pluripotent stem cell lines of TRPC1 knockout by CRISPR/Cas9. We demonstrated that knockout of TRPC1 significantly attenuated cardiomyocyte hypertrophy phenotype induced by phorbol 12-myristate 13-acetate, which was associated with abnormal activation of NF-κB. In contrast, overexpression of TRPC1 induced cardiomyocyte hypertrophy, which can be reversed by inhibition of NF-κB. Taken together, we established a stable human-based cardiomyocyte hypertrophy model and highlighted molecular mechanisms underlying TRPC1-mediated hypertrophy, aiding the development of therapeutic drugs for HCM and HF by targeting TRPC1.