SHP2 mediates gp130-dependent cardiomyocyte hypertrophy via negative regulation of skeletal alpha-actin gene.

Abstract

Morphological and biochemical phenotypes of cardiomyocyte hypertrophy are determined by neurohumoral factors. Stimulation of G protein-coupled receptor (GPCR) results in uniform cell enlargement in all directions with an increase in skeletal alpha-actin (alpha-SKA) gene expression, while stimulation of gp130 receptor by interleukin-6 (IL-6)-related cytokines induces longitudinal elongation with no increase in alpha-SKA gene expression. Thus, alpha-SKA is a discriminating marker for hypertrophic phenotypes; however, regulatory mechanisms of alpha-SKA gene expression remain unknown. Here, we clarified the role of SH2-containing protein tyrosine phosphatase 2 (SHP2) in alpha-SKA gene expression. In neonatal rat cardiomyocytes, endothelin-1 (ET-1), a GPCR agonist, but not leukemia inhibitory factor (LIF), an IL-6-related cytokine, induced RhoA activation and promotes alpha-SKA gene expression via RhoA. In contrast, LIF, but not ET-1, induced activation of SHP2 in cardiomyocytes, suggesting that SHP2 might negatively regulate alpha-SKA gene expression downstream of gp130. Therefore, we examined the effect of adenovirus-mediated overexpression of wild-type SHP2 (SHP2(WT)), dominant-negative SHP2 (SHP2(C/S)), or beta-galactosidase (beta-gal), on alpha-SKA gene expression. LIF did not upregulate alpha-SKA mRNA in cardiomyocytes overexpressing either beta-gal or SHP2(WT). In cardiomyocytes overexpressing SHP2(C/S), LIF induced upregulation of alpha-SKA mRNA, which was abrogated by concomitant overexpression of either C3-toxin or dominant-negative RhoA. RhoA was activated after LIF stimulation in the cardiomyocytes overexpressing SHP2(C/S), but not in myocytes overexpressing beta-gal. Furthermore, SHP2 mediates LIF-induced longitudinal elongation of cardiomyocytes via ERK5 activation. Collectively, these findings indicate that SHP2 negatively regulates alpha-SKA expression via RhoA inactivation and suggest that SHP2 implicates ERK5 in cardiomyocyte elongation downstream of gp130.

• Authors: Yoshikazu Nakaoka, Wataru Shioyama, Satoshi Kunimoto, Yoh Arita, Kaori Higuchi, Kaori Yamamoto, Yasushi Fujio, Keigo Nishida, Tadashi Kuroda, Hisao Hirota, Keiko Yamauchi-Takihara, Toshio Hirano, Issei Komuro, Naoki Mochizuki
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 49 Issue 2 Pg. 157-64 (Aug 2010) ISSN: 1095-8584 [Electronic] England
• PMID: 20226789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Endothelin-1
• Leukemia Inhibitory Factor
• RNA, Messenger
• Cytokine Receptor gp130
• Mitogen-Activated Protein Kinase 7
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• rhoA GTP-Binding Protein

Topics

• Actins (genetics)
• Animals
• Animals, Newborn
• Cardiomegaly (enzymology, genetics)
• Cell Shape (drug effects)
• Cytokine Receptor gp130 (metabolism)
• Endothelin-1 (pharmacology)
• Enzyme Activation (drug effects)
• Gene Expression Regulation (drug effects)
• Leukemia Inhibitory Factor (pharmacology)
• Mitogen-Activated Protein Kinase 7 (metabolism)
• Models, Biological
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (metabolism)
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)
• Up-Regulation (drug effects)
• rhoA GTP-Binding Protein (metabolism)