MYH7 R453C Induced Cardiac Remodeling via Activating TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB Signaling Pathways

Hypertrophic cardiomyopathy (HCM) is a monogenic cardiac disorder commonly induced by sarcomere gene mutations. However, the mechanism for HCM is not well defined. Here, we generated transgenic MYH7 R453C and MYH6 R453C piglets and found they both developed typically cardiac hypertrophy. Unexpectedly, we found serious fibrosis and cardiomyocyte loss in the ventricular of MYH7 R453C, not MYH6 R453C piglets similar to HCM patients. Then RNA-seq analysis and western blotting identified the activation of ERK1/2 and PI3K-Akt pathways in MYH7 R453C. Expected the increased expression of fetal gene, we noticed the excessed ROS in MYH7 R453C piglet models produced by Nox4 and they subsequently induced inflammation response. In addition, the phosphorylated Smad2/3, ERK1/2, and NF-kB p65 protein in the MYH7 R453C mutation cardiomyocytes reinforced. Furthermore, EGCG, a natural bioactive compound, could be used as a drug to reduce cell death by adjusting significant downregulation of the protein expression of Bax and upregulated Bcl-2 levels in the H9C2 models with MYH7 R453C mutation. In conclusion, our study illustrated that TGF-β/Smad2/3, ERK1/2, and Nox4/ROS pathways have synergistic effects on cardiac remodeling and inflammation in MYH7 R453C mutation.