Chirag H Mandavia
Impaired insulin signaling in conditions of over-nutrition and obesity leading to insulin resistance is a major component of the cardiorenal metabolic syndrome and leads to the development of diabetes and Cardiovascular Disease (CVD). Dysregulation of the Renin-Angiotensin-Aldosterone (RAAS) axis is thought to play a major contributory role to the development of insulin resistance in overweight and obesity. The Insulin Receptor Substrate protein 1 (IRS-1) is a critical signaling and docking molecule in the insulin signaling pathway. IRS-1 mediates both upstream and downstream components of the insulin signaling cascade through binding of the Insulin Receptor (IR) to its N-terminus, as also allowing docking of the p85 subunit of Phosphatidylinositol 3-Kinase (PI3K) upon tyrosine phosphorylation, thereby facilitating glucose uptake through phosphorylation of protein kinase B (Akt). IRS-1 is tightly regulated principally through the mechanism of phosphorylation and has been known to undergo proteasomal degradation in the cytosol upon excessive serine-threonine phosphorylation on its residues. Multiple stimuli, including components of the RAAS, namely angiotensin, and aldosterone, as well as several different serine kinases acting through different pathways, have been shown to play a role in IRS-1 mediated degradation. In recent years, aldosterone has emerged as a key modulator of the insulin metabolic pathway, primarily through its ability to cause cellular oxidative stress leading to degradation of IRS-1, thus reducing glucose uptake. However, to date, no studies have been carried out on the effect of aldosterone in cardiac cells. Since insulin resistance is a major factor in the development of CVD, we show here time and dosedependent degradation of IRS-1 by aldosterone in HL-1 cardiomyocytes, using over-expression studies of fluorescentlylabeled recombinant IRS-1 protein. We further show, through the use of the mineralocorticoid receptor (MR)-specific antagonist eplerenone, that this effect is mediated primarily by the Glucocorticoid Receptor (GR), mostly by causing increased oxidative stress and rendering the cardiomyocytes susceptible to impaired cellular function and damage
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Journal of Metabolic Syndrome received 48 citations as per Google Scholar report
