Altered Tyrosine Phosphorylation of Cardiac Proteins Prompts Contractile Dysfunction in Hypertrophic Cardiomyopathy

Abstract

Altered Serine/Threonine phosphorylation of the cardiac proteome is an established hallmark of heart failure (HF). However, the contribution of tyrosine phosphorylation to the pathogenesis of these diseases remains unclear. The cardiac proteome was explored by global mapping to discover and quantify site-specific tyrosine phosphorylation in two cardiac hypertrophic models; cardiac overexpression of ErbB2 (TgErbB2) and cardiac expression of α-Myosin heavy chain R403Q (R403Q-αMyHCTg) compared to control hearts. Phosphoproteomic changes found in R403Q-αMyHC Tg mice indicated EGFR1, Focal Adhesion, VEGF, ErbB signaling, and Chemokine signaling pathways activity were likely to be activated. On the other hand, TgErbB2 mice findings displayed significant overrepresentation of Right Ventricular Cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) KEGG Pathways. In silico kinase-substrate enrichment analysis (KSEA) highlighted a marked downregulation of canonical MAPK Pathway Activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, PP2 inhibition of c-Src, and Hepatocyte growth factor stimulation. In vivo ErbB2 inhibition by AG-825 decreased cardiac fibrosis, cardiomyocyte disarray, and rescued contractile function on TgErbB2 mice. These results suggest that altered tyrosine phosphorylation may play a regulatory role in cardiac hypertrophic models, suggesting that tyrosine kinase inhibitors could be used therapeutically in Hypertrophic Cardiomyopathy.

Signaling network model of cardiomyocyte morphological changes in familial cardiomyopathy

“…Regarding the main signaling modules, Davis et al 11 indicated the myofilament force-generation module, CaN-NFAT, and ERK1/2 pathways regulate mass and eccentricity in familial cardiomyopathy. In addition, other signaling pathways such as PI3K-AKT 14,21 , NO-PKG 15,26 , calcium 27 , β-adrenergic 13,28 , and downstream pathways of Gq protein 29 and growth factor receptors 30,31 could play a role in familial cardiomyopathy. Moreover, titin has been described as a regulator of familial cardiomyopathy via its effects on cardiomyocyte stiffness, force generation 32 , and mechanotransduction 33 .…”

Machine Learning Models identify Signature Genes as potential Biomarkers for Hypertrophic Cardiomyopathy from Williams Syndrome

“…We also found the DEGs between two clusters were mainly involved in cell adhesion molecules cams, Ecm receptor interaction, focal adhesion, oxidative phosphorylation, regulation of actin cytoskeleton and tight junction. Previous studies have reported the altered tyrosine phosphorylation may play a regulatory role in cardiac hypertrophic models [23]. Tyrosine/serine phosphorylated focal adhesion kinase are required for the hypertrophic response of cardiomyocytes to growth factors and mechanical load that may explained the machanism of cell spreading and sarcomere reorganization in HCM [24].…”

“…Williams syndrome (WS) is a rare inherited multi-system disease which caused by < 2-megabase pair (Mb) deletion of chromosome 7q11. 23. It occurs in as many as 1:7500-25000 individuals [6].…”