ANG II inhibits insulin-mediated production of PI 3,4,5-trisphosphates via a Ca²⁺-dependent but PKC-independent pathway in the cardiomyocytes

Abstract

Insulin resistance (IR) is a condition where different organs are refractory to insulin stimulation of glucose uptake. ANG II has been suggested to be involved in the development of IR in the heart. The precise mechanism by which this occurs is still unknown. Here we have used dynamic fluorescent imaging techniques to show that ANG II inhibits insulin production of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P(3)] in cardiac myocytes. Fluorophore (Venus)-conjugated cAMP-dependent protein kinase-pleckstrin homology domain, which specifically binds to PI(3,4,5)P(3), was transfected in neonatal rat cardiac myocytes. Insulin induced a robust increase in the fluorescence intensity at the cell surface, which was diminished by application of ANG II. The inhibitory action of ANG II was antagonized by RNH-6270 (an angiotensin type 1 receptor antagonist) but not by PD-122370 (an angiotensin type 2 receptor antagonist). BAPTA-AM (Ca(2+) chelator) largely attenuated the ANG II effect, whereas K-252b (PKC inhibitor) did not. Furthermore, an elevation of intracellular Ca(2+) induced by ionomycin mimicked the ANG II effect. Therefore, it is suggested that ANG II antagonizes insulin-mediated production of PI(3,4,5)P(3) via a Ca(2+)-dependent but PKC-independent pathway in cardiac myocytes.

ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4

“…To assess cardiac insulin resistance in ANG II-induced hypertrophied hearts, the expressions of phosphorylation of Akt were determined. Akt is an important kinase in the insulin signaling pathway and ANG II can lead to dephosphorylation of Akt and impairment in insulin signaling (9,16). We showed that ANG II was associated with whole-body insulin resistance as determined by the OGTT (Fig.…”

“…ANG II-induced myocardial hypertrophy, insulin resistance, and diastolic dysfunction predispose the heart to the development of heart failure (15,26,39) and mimic the LV diastolic dysfunction seen in diabetic cardiomyopathy (3,5). ANG II-induced insulin resistance has been reported in adipocyte, vascular smooth muscle cells, and cardiac myocytes (7,16,22) and is likely due to dephosphorylation and inactivation of Akt (9,16), leading to impairment in insulin signaling.…”