FOXC1-FTO axis regulates cardiomyocyte hypertrophy and mitochondrial dysfunction during cardiac hypertrophy in mice.

Cardiomyocyte hypertrophy and mitochondrial dysfunction represent the primary outcomes of pathological myocardial hypertrophy. Although FOXC1 has been reported to be associated with myocardial injury, its functional role in cardiac hypertrophy remains unclear. FOXC1 was found to be upregulated in both transverse aortic constriction (TAC)-induced cardiac hypertrophy mice and angiotensin II (Ang II)-induced cardiomyocytes (AC16 cells), suggesting that high expression of FOXC1 might serve as a risk factor in the progression of myocardial hypertrophy. To investigate the effect of FOXC1 on cardiomyocyte injury, FOXC1 siRNA was designed and transfected into cardiomyocytes. Knocking down FOXC1 suppressed the occurrence of hypertrophic responses, including the reduction in the levels of hypertrophic markers (atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) and the increase in cardiomyocyte surface area. Additionally, FOXC1 knockdown alleviated mitochondrial dysfunction in cardiomyocytes, as evidenced by the decrease in oxidative stress levels and mitochondrial membrane potential. Mechanistically, FOXC1 was found to inhibit the transcriptional activity of FTO, and FTO inhibition exacerbated the myocardial injury relieved by FOXC1 knockdown. Collectively, our study highlighted the functional role of FOXC1 in the pathogenesis of myocardial hypertrophy and provided a potential target for the prevention and treatment of pathological myocardial hypertrophy.