Abstract 12873: Selective Inhibition of PKCa and β Attenuates Glucose-Induced Potentiation of Vasoconstriction in Human Internal Mammary Arteries
Acute hyperglycemia is a marker of adverse prognosis in patients presenting with acute myocardial infarction (MI) irrespective of a previous diagnosis of diabetes mellitus. Hyperglycemia also increases the risk of coronary no-reflow during primary angioplasty for ST-elevation MI. The molecular mechanism underlying these effects is poorly understood. We have previously demonstrated elevated glucose inhibits vasodilatory K+-flux in rat vascular smooth muscle in a PKC-dependent mechanism. The relative importance of different PKC isoforms to hyperglycemic vasoconstriction has not previously been investigated. We demonstrate hyperglycemia in human vessels exacerbates vasoconstrictor responses in a PKCα and β-dependent mechanism.
Human internal mammary arterial rings obtained during coronary artery bypass graft were mounted on a wire myograph and contraction in response to 60mM K+ (60K), angiotensin-II (AT-II) and U46619 (thromboxane-A2 agonist) assessed in 5 and 20mM glucose. Data were expressed normalized to tension and arterial diameter (mN/mm).
Consistent with findings in other vascular tissue, the contraction in 20mM glucose to 60K, AT-II and U46619 was markedly potentiated compared to 5mM glucose (4.2±0.7 v 1.4±0.3mN/mm (60K), 1.4±0.3 v 4.8±0.8mN/mm (AT-II) and 1.3±0.4 v 5.4±0.9mN/mm (U46619) in 5 and 20mM glucose respectively (n=6-10 vessels from 4 patients for each data set). This potentiation of vasoconstriction in 20mM glucose was reversed by pre-incubation with 300nM Gö6976 (PKCα and β inhibitor) (1.7±0.5, 1.0±0.5 and 1.1±0.3mN/mm 60K, AT-II and U46619 respectively (P≤0.01 for each inhibitor compared to 20mM). Selective inhibition of PKCβ alone using LY379196 partly attenuated the potentiated vasoconstriction in 20mM glucose (2.2±0.5, 1.9±0.5 and 2.8±0.7mN/mm 60K, AT-II and U46619 respectively, P≤0.05 for AT-II and U46619 compared to 20mM glucose).
Our data provide compelling evidence that inhibition of PKCα and β reverses the potentially deleterious increase in contractile responsiveness seen in blood vessels with elevated extracellular glucose concentrations. This approach has potential therapeutic application to reduce the adverse effect of hyperglycemia in patients presenting with acute MI.
- © 2013 by American Heart Association, Inc.