Co-activation of nuclear factor-κB and myocardin/serum response factor conveys the hypertrophy signal of high insulin levels in cardiac myoblasts.

Abstract

Hyperinsulinemia contributes to cardiac hypertrophy and heart failure in patients with the metabolic syndrome and type 2 diabetes. Here, high circulating levels of tumor necrosis factor (TNF)-α may synergize with insulin in signaling inflammation and cardiac hypertrophy. We tested whether high insulin affects activation of TNF-α-induced NF-κB and myocardin/serum response factor (SRF) to convey hypertrophy signaling in cardiac myoblasts. In canine cardiac myoblasts, treatment with high insulin (10(-8) to 10(-7) m) for 0-24 h increased insulin receptor substrate (IRS)-1 phosphorylation at Ser-307, decreased protein levels of chaperone-associated ubiquitin (Ub) E3 ligase C terminus of heat shock protein 70-interacting protein (CHIP), increased SRF activity, as well as β-myosin heavy chain (MHC) and myocardin expressions. Here siRNAs to myocardin or NF-κB, as well as CHIP overexpression prevented (while siRNA-mediated CHIP disruption potentiated) high insulin-induced SR element (SRE) activation and β-MHC expression. Insulin markedly potentiated TNF-α-induced NF-κB activation. Compared with insulin alone, insulin+TNF-α increased SRF/SRE binding and β-MHC expression, which was reversed by the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and by NF-κB silencing. In the hearts of db/db diabetic mice, in which Akt phosphorylation was decreased, p38MAPK, Akt1, and IRS-1 phosphorylation at Ser-307 were increased, together with myocardin expression as well as SRE and NF-κB activities. In response to high insulin, cardiac myoblasts increase the expression or the promyogenic transcription factors myocardin/SRF in a CHIP-dependent manner. Insulin potentiates TNF-α in inducing NF-κB and SRF/SRE activities. In hyperinsulinemic states, myocardin may act as a nuclear effector of insulin, promoting cardiac hypertrophy.

• Authors: Rosalinda Madonna, Yong-Jian Geng, Roberto Bolli, Gregg Rokosh, Peter Ferdinandy, Cam Patterson, Raffaele De Caterina
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 28 Pg. 19585-98 (Jul 11 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24855642 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antineoplastic Agents
• Insulin
• NF-kappa B
• Nuclear Proteins
• Serum Response Factor
• Thiocarbamates
• Trans-Activators
• Tumor Necrosis Factor-alpha
• myocardin
• prolinedithiocarbamate
• Proline
• Stub1 protein, mouse
• Ubiquitin-Protein Ligases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cardiomegaly (chemically induced, genetics, metabolism, pathology)
• Cells, Cultured
• Dogs
• Gene Expression Regulation (drug effects, genetics)
• Insulin (metabolism)
• Mice
• Myoblasts, Cardiac (metabolism, pathology)
• NF-kappa B (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Proline (analogs & derivatives, pharmacology)
• Serum Response Factor (genetics, metabolism)
• Thiocarbamates (pharmacology)
• Trans-Activators (genetics, metabolism)
• Tumor Necrosis Factor-alpha (toxicity)
• Ubiquitin-Protein Ligases (biosynthesis, genetics)