Title: No-flow ischemia inhibits insulin signaling in heart by decreasing intracellular pH
Authors: Beauloye, C ×
Bertrand, L
Krause, U
Marsin, A S
Dresselaers, Tom
Vanstapel, Florent
Vanoverschelde, J L
Hue, L #
Issue Date: Mar-2001
Publisher: Lippincott Williams & Wilkins
Series Title: Circulation Research vol:88 issue:5 pages:513-9
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 (pH(i)) 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 pH(i) and insulin signaling, whereas perfusing at pH 8.2 counteracted the drop in pH(i) 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 pH(i), 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 pH(i).
ISSN: 0009-7330
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Biomedical MRI
Laboratory of Clinical Bacteriology and Mycology
Biomedical Quality Assurance Research Unit
× corresponding author
# (joint) last author

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