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. (Circ Heart Fail.

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

“…Mice lacking Foxo1 in the heart displayed almost normal cardiac growth and function (Qi et al 2015), and Foxo1 inactivation partially rescued cardiac dysfunction and death in mice lacking cardiac IRS-1 and IRS-2 (Qi et al 2015), with similar results observed in db/db mice (Battiprolu et al 2012). In particular, we demonstrated the key role of Foxo1 in stimulating cardiac dysfunction by promoting β-myosin heavy chain (β-MHC) gene expression, a myocardial structural gene responsible for reduction in cardiac contractility (Qi et al 2015).…”

“…Mice lacking Foxo1 in the heart displayed almost normal cardiac growth and function (Qi et al 2015), and Foxo1 inactivation partially rescued cardiac dysfunction and death in mice lacking cardiac IRS-1 and IRS-2 (Qi et al 2015), with similar results observed in db/db mice (Battiprolu et al 2012). In particular, we demonstrated the key role of Foxo1 in stimulating cardiac dysfunction by promoting β-myosin heavy chain (β-MHC) gene expression, a myocardial structural gene responsible for reduction in cardiac contractility (Qi et al 2015). Although diminished activity of Akt in animal hearts with T2D may enhance Foxo1-dependent gene expression responsible for atrophy, autophagy and apoptosis in many cells, which contribute to organopathy (Guo 2014), appropriate expression of Foxo1 promotes autophagy and anti-oxidative gene expression that is beneficial to the heart (Sengupta et al 2009(Sengupta et al , 2011.…”

“…IRS-1 and IRS-2 are critical for adult cardiac homeostasis and function, via a suppression of Foxo1 or activation of mTORC1 downstream from PDK1 and Akt, evidenced by that suppression of IRS-1 and IRS-2 in adult heart caused Foxo1 activation, reduction in mTORC1 and cardiac dysfunction (Qi et al 2015). During early embryogenesis, however, PDK1 activity is not required for the cardiac development (Mora et al 2003).…”

“…During early embryogenesis, however, PDK1 activity is not required for the cardiac development (Mora et al 2003). Similarly, Foxo1 is important for angiogenesis during vascular developmental stage but not necessary for the cardiac development (Hosaka et al 2004, Qi et al 2015. Overexpression of cardiac Foxo1 in mouse embryos prevents cell proliferation and heart development (Evans- Anderson et al 2008).…”

“…Fetal gene programming, energy metabolism and heart failure Activation of fetal gene profiling is characteristic of cardiac remodeling and heart failure (Dirkx et al 2013), including β-MHC, a Foxo1 target gene we have recently identified (Qi et al 2015). Reprogramming of fetal gene expression was found in adverse cardiac remodeling and biomechanical stresses in failing or aging hearts (Marber et al 2010, Koitabashi & Kass 2012.…”