Activation of Foxo1 by insulin resistance promotes cardiac dysfunction and β-myosin heavy chain gene expression.

Abstract

BACKGROUND:

Heart failure is a leading cause of morbidity and mortality in the USA and is closely associated with diabetes mellitus. The molecular link between diabetes mellitus and heart failure is incompletely understood. We recently demonstrated that insulin receptor substrates 1, 2 (IRS1, 2) are key components of insulin signaling and loss of IRS1 and IRS2 mediates insulin resistance, resulting in metabolic dysregulation and heart failure, which is associated with downstream Akt inactivation and in turn activation of the forkhead transcription factor Foxo1.

METHODS AND RESULTS:

To determine the role of Foxo1 in control of heart failure in insulin resistance and diabetes mellitus, we generated mice lacking Foxo1 gene specifically in the heart. Mice lacking both IRS1 and IRS2 in adult hearts exhibited severe heart failure and a remarkable increase in the β-isoform of myosin heavy chain (β-MHC) gene expression, whereas deletion of cardiac Foxo1 gene largely prevented the heart failure and resulted in a decrease in β-MHC expression. The effect of Foxo1 deficiency on rescuing cardiac dysfunction was also observed in db/db mice and high-fat diet mice. Using cultures of primary ventricular cardiomyocytes, we found that Foxo1 interacts with the promoter region of β-MHC and stimulates gene expression, mediating an effect of insulin that suppresses β-MHC expression.

CONCLUSIONS:

Our study suggests that Foxo1 has important roles in promoting diabetic cardiomyopathy and controls β-MHC expression in the development of cardiac dysfunction. Targeting Foxo1 and its regulation will provide novel strategies in preventing metabolic and myocardial dysfunction and influencing MHC plasticity in diabetes mellitus.

• Authors: Yajuan Qi, Qinglei Zhu, Kebin Zhang, Candice Thomas, Yuxin Wu, Rajesh Kumar, Kenneth M Baker, Zihui Xu, Shouwen Chen, Shaodong Guo
• Journal: Circulation. Heart failure (Circ Heart Fail) Vol. 8 Issue 1 Pg. 198-208 (Jan 2015) ISSN: 1941-3297 [Electronic] United States
• PMID: 25477432 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• Myh7 protein, mouse
• RNA
• Myosin Heavy Chains

Topics

• Animals
• Blotting, Western
• Cells, Cultured
• Diabetes Mellitus, Experimental
• Diabetic Cardiomyopathies (genetics, metabolism, physiopathology)
• Forkhead Box Protein O1
• Forkhead Transcription Factors (metabolism)
• Gene Expression Regulation
• Immunoprecipitation
• Insulin Resistance (genetics)
• Mice
• Mice, Inbred C57BL
• Microscopy, Electron
• Myocytes, Cardiac (metabolism, ultrastructure)
• Myosin Heavy Chains (biosynthesis, genetics)
• RNA (genetics)
• Real-Time Polymerase Chain Reaction
• Ventricular Function, Left (physiology)