Cirrhosis Promotes Cardiac Fibrosis Development by Inhibiting Notch1 in Cardiac Fibroblasts

Cardiovascular disease risk is elevated in patients with cirrhosis. However, the underlying molecular mechanisms remain poorly understood. Herein, we found that high levels of circulating transforming growth factor (TGF)-β1 were associated with an increased risk of cardiomyopathy in cirrhosis patients. Similarly, we confirmed that high circulating TGF-β1 elevated the progress of cardiac fibrosis in cirrhosis mice. Furthermore, elevated circulating TGF-β1 reduced Notch1 expression, increased glycolysis, promoted fibroblast proliferation and migration, and induced cardiac fibrosis. Interestingly, deletion of Notch1 exacerbated the progress of cardiac fibrosis in cirrhosis mice. Mechanistically, TGF-β1 elevated the DNA methylation levels in the Notch1 promoter by enhancing DNMT3A expression. Increased methylated CpGs then recruited the MeCP2 and suppressed Notch1 transcription. Reactivation of Notch1 through the knockdown of either DNMT3A or MeCP2 ameliorated glycolysis, proliferation, migration, and cardiac fibrosis in cardiac fibroblasts. Our study demonstrates that cirrhosis-induced high levels of circulating TGF-β1 increase the progress of cardiac fibrosis through the inhibition of Notch1 in a DNA methylation-dependent mechanism. These findings provide insights into the development of preventative measures for cirrhosis-induced cardiac fibrosis risk.