Journal Article

MYH7 R453C induced cardiac remodelling via activating TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB signalling pathways

Ouyang, Hongsheng, Chen, Jiahuan, Zhao, Dazhong, Li, Linquan, Zhang, Huanyu, Pang, Daxin, Yuan, Hongming, Lu, Yi, Wang, Lingyu

2024

Overview

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 both developed typical 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. Moreover, we observed an increased expression of fetal genes and an excess of reactive oxygen species (ROS) in MYH7 R453C piglet models, which was produced by Nox4 and subsequently induced inflammatory response. Additionally, the phosphorylation levels of Smad2/3, ERK1/2 and NF-kB p65 proteins were elevated in cardiomyocytes with the MYH7 R453C mutation. Furthermore, epigallocatechin gallate, 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 remodelling and inflammation in MYH7 R453C mutation.

• Publisher: The Royal Society,The Royal Society Publishing
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Animal models / Animals / Animals, Genetically Modified / BAX protein / Bcl-2 protein / Bioactive compounds / Cardiac Myosins - genetics / Cardiac Myosins - metabolism / Cardiac Remodelling / Cardiomyocytes / Cardiomyopathy / Cardiomyopathy, Hypertrophic - genetics / Cardiomyopathy, Hypertrophic - metabolism / Cardiomyopathy, Hypertrophic - pathology / Cell culture / Cell death / Disease / Disease Models, Animal / EGCG / Epigallocatechin gallate / Extracellular signal-regulated kinase / Females / Fetuses / Fibroblasts / Fibrosis / Heart / Hogs / Humans / Hypertrophic Cardiomyopathy / Hypertrophy / Inflammation / Kinases / MAP Kinase Signaling System / Mutation / MYH7 R453C / Myocytes, Cardiac - metabolism / Myosin Heavy Chains - genetics / Myosin Heavy Chains - metabolism / NADPH Oxidase 4 - genetics / NADPH Oxidase 4 - metabolism / NF-kappa B - metabolism / NF-κB protein / NOX4 protein / Oxidative stress / Phosphorylation / Plasmids / Point mutation / Proteins / Rats / Reactive oxygen species / Reactive Oxygen Species - metabolism / Signal Transduction / Smad2 Protein - genetics / Smad2 Protein - metabolism / Smad3 Protein - genetics / Smad3 Protein - metabolism / Swine / Transforming Growth Factor beta - metabolism / Transforming growth factor-b / Ventricular Remodeling / Western blotting