© 2001 American Heart Association, Inc.
Integrative Physiology |
No-Flow Ischemia Inhibits Insulin Signaling in Heart by Decreasing Intracellular pH
From the Division of Cardiology (C.B., J.-L.V.), and Hormone and Metabolic Research Unit (C.B., L.B., U.K., A.-S.M., L.H.), Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Brussels, and Biomedical Nuclear Magnetic Resonance Unit (T.D., F.V.), Department of Radiology, Katholieke Universiteit Leuven, Belgium.
Correspondence to Prof L. Hue, HORM Unit, 75, Ave Hippocrate, ICP-UCL 7529, B-1200 Brussels, Belgium. E-mail hue{at}horm.ucl.ac.be
Abstract—Glucose-insulin-potassium solutions exert beneficial effects on the ischemic heart by reducing infarct size and mortality and improving postischemic left ventricular function. Insulin could be the critical protective component of this mixture, although the insulin response of the ischemic and postischemic myocardium has not been systematically investigated. The aim of this work was to study the insulin response during ischemia by analyzing insulin signaling. This was evaluated by measuring changes in activity and/or phosphorylation state of insulin signaling elements in isolated perfused rat hearts submitted to no-flow ischemia. Intracellular pH (pHi) was measured by NMR. No-flow ischemia antagonized insulin signaling including insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, protein kinase B, p70 ribosomal S6 kinase, and glycogen synthase kinase-3. These changes were concomitant with intracellular acidosis. Perfusing hearts with ouabain and amiloride in normoxic conditions decreased pHi and insulin signaling, whereas perfusing at pH 8.2 counteracted the drop in pHi and the inhibition of insulin signaling by ischemia. Incubation of cardiomyocytes in normoxic conditions, but at pH values below 6.75, mimicked the effect of ischemia and also inhibited insulin-stimulated glucose uptake. Finally, the in vitro insulin receptor tyrosine kinase activity was progressively inhibited at pH values below physiological pHi, being abolished at pH 6.0. Therefore, ischemic acidosis decreases kinase activity and tyrosine phosphorylation of the insulin receptor thereby preventing activation of the downstream components of the signaling pathway. We conclude that severe ischemia inhibits insulin signaling by decreasing pHi.
Key Words: ischemia • insulin • signal transduction • glucose • acidosis
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