Alteration in tyrosine phosphorylation of cardiac proteome and EGFR pathway contribute to hypertrophic cardiomyopathy

• Published in: Communications biology 2022-11, Vol.5 (1), p.1251-1251, Article 1251
• Main Authors: Xu, Mingguo, Bermea, Kevin C., Ayati, Marzieh, Kim, Han Byeol, Yang, Xiaomei, Medina, Andres, Fu, Zongming, Heravi, Amir, Zhang, Xinyu, Na, Chan Hyun, Everett, Allen D., Gabrielson, Kathleen, Foster, D. Brian, Paolocci, Nazareno, Murphy, Anne M., Ramirez-Correa, Genaro A.
• Format: Article
• Language: English
• Subjects: 13/1; 631/45/475; 692/4019/592/1540; 82/58; Actin; Angiopoietin; Animal models; Animals; Biology; Biomedical and Life Sciences; Cardiomegaly; Cardiomyocytes; Cardiomyopathy; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - metabolism; Cardiomyopathy, Hypertrophic - pathology; Chemokines; Congestive heart failure; Cytoskeleton; Dilated cardiomyopathy; Epidermal growth factor receptors; ErbB protein; ErbB-2 protein; Growth hormones; Hypertrophy; Kinases; Life Sciences; MAP kinase; Mice; Myosin; Phosphorylation; Phosphotyrosine; Protein-tyrosine kinase; Proteome - metabolism; Proteomes; Proteomics; Serine; Serine - metabolism; Threonine; Threonine - metabolism; Tyrosine - metabolism; Ventricle
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-04021-4

Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac overexpression of ErbB2 (TgErbB2) and α myosin heavy chain R403Q (R403Q-αMyHC Tg), compared to control hearts. From this, there are significant phosphoproteomic alterations in TgErbB2 mice in right ventricular cardiomyopathy, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) pathways. On the other hand, R403Q-αMyHC Tg mice indicated that the EGFR1 pathway is central for cardiac hypertrophy, along with angiopoietin, ErbB, growth hormone, and chemokine signaling pathways activation. Surprisingly, most myofilament proteins have downregulation of pTyr rather than upregulation. Kinase-substrate enrichment analysis (KSEA) shows a marked downregulation of MAPK pathway activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, focal adhesion, PDGFR, and actin cytoskeleton pathways. In vivo ErbB2 inhibition by AG-825 decreases cardiomyocyte disarray. Serine/threonine and tyrosine phosphoproteome confirm the above-described pathways and the effectiveness of AG-825 Treatment. Thus, altered pTyr may play a regulatory role in cardiac hypertrophic models. Quantitative global phosphotyrosine proteomics of two mouse models of hypertrophic cardiomyopathy reveals that tyrosine kinase inhibitors may be a future therapeutic approach for treating hypertrophic cardiomyopathy.