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Insulin inhibits coronary endothelial cell calcium entry and coronary artery relaxation
1Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
Insights
High-dose insulin acutely impairs coronary endothelial cell function and reduces coronary artery relaxation by inhibiting calcium signaling. This suggests hyperinsulinemia may contribute to coronary artery disease through endothelial dysfunction.
Area of Science:
- Cardiovascular Research
- Endothelial Cell Biology
- Metabolic Disease Research
Background:
- Hyperinsulinemia is linked to coronary artery disease (CAD).
- Endothelial cell dysfunction is implicated in CAD.
- The direct impact of insulin on coronary endothelial cells remains unclear.
Purpose of the Study:
- To investigate the acute effects of high-dose insulin on coronary endothelial cells.
- To determine insulin's influence on intracellular calcium concentration ([Ca(2+)](i)) and coronary vasodilation.
Main Methods:
- Porcine coronary endothelial cells and artery rings were used.
- Agonist-induced [Ca(2+)](i) and vasodilation were measured.
- Cells and tissues were preincubated with varying doses of insulin.
Main Results:
- High-dose insulin (10-100 mU/ml) dose-dependently inhibited agonist-induced [Ca(2+)](i) increases in coronary endothelial cells.
- Insulin attenuated agonist-induced relaxation in coronary artery rings.
- These effects were not observed at physiological insulin concentrations.
Conclusions:
- High-dose insulin acutely inhibits calcium signaling in coronary endothelial cells.
- Insulin attenuates agonist-induced coronary vasodilation.
- Hyperinsulinemia may contribute to CAD by disrupting endothelial calcium-dependent functions.
Abstract:
Hyperinsulinemia is closely related to coronary artery disease. Endothelial cells are important for the control of vascular tone, and dysfunction of endothelial cells has been implicated in coronary artery disease. The direct effects of insulin on coronary endothelial cells are nonetheless unknown. In this study, the acute effects of high-dose insulin were investigated on agonist-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) in porcine coronary endothelial cells and coronary relaxation. Bradykinin (10 n M ) and cyclopiazonic acid (100 microM), an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, provoked large increases in [Ca(2+)](i) in coronary endothelial cells. This increase was dose-dependently inhibited by a 10-min preincubation with high doses of insulin (10, 30, 100 mU/ml). Under Ca(2+)-free conditions, bradykinin and cyclopiazonic acid provoked transient, small increases in [Ca(2+)](i). These increases were not affected by pretreatment with insulin (100 mU/ml). Bradykinin (1, 10, 100, 1,000 n M ) and cyclopiazonic acid (10 microM) significantly relaxed porcine coronary artery rings precontracted with histamine (1 microM). The vasodilator effects of bradykinin and cyclopiazonic acid were dose-dependently inhibited by insulin. These acute effects were not observed at physiologic concentrations. Our data indicate that high-dose insulin inhibits agonist-induced Ca(2+) response in coronary endothelial cells and attenuates agonist-induced coronary vasodilatation. The study suggests that hyperinsulinemia might be associated with coronary artery disease via derangement of endothelial Ca(2+)-dependent functions.