Inhibition of glycogen synthase kinase-3beta improves tolerance to ischemia in hypertrophied hearts.

Background: Hypertrophied myocardium is more susceptible to ischemia/reperfusion injury, in part owing to impaired insulin-mediated glucose uptake. Glycogen synthase kinase-3beta (GSK-3beta) is a key regulatory enzyme in glucose metabolism that, when activated, phosphorylates/inactivates target enzymes of the insulin signaling pathway. Glycogen synthase kinase-3beta is regulated upstream by Akt-1.

Cyclosporin A but not FK-506 protects against dopamine-induced apoptosis in the stunned heart.

Background: Dopamine given at moderate doses for inotropy to postischemic hearts has been shown to augment myocyte apoptosis in association with elevated cytosolic calcium. We hypothesize that dopamine-mediated apoptosis occurs through calcium-induced opening of the mitochondrial permeability transition (mPT) pore. We also hypothesize that cyclosporin A (CSA), a calcineurin inhibitor known to block mPT pore opening, would prevent dopamine-induced apoptosis primarily by inhibiting pore opening (cyclophilin D binding).

Impaired insulin-signaling in hypertrophied hearts contributes to ischemic injury.

Despite increased glucose utilization by hypertrophied myocardium, these hearts exhibit a slower rate of glucose uptake (GU). We hypothesized that, in hypertrophied myocardium, a defect of the insulin-responsive glucose transporter is responsible for impaired GU and metabolism during ischemia, contributing to post-ischemic myocardial dysfunction. In a rabbit model of pressure-overload hypertrophy, GU ((31)P NMR spectroscopy) and total/phosphorylated insulin-signaling intermediates were assayed: insulin-receptor, insulin-receptor-substrate-1 (IRS-1), phosphatidylinositol-3-kinase (PI3-k), GLUT-4 translocation and contractile function in an isolated heart ischemia/reperfusion model.

Postnatal increase in insulin-sensitive glucose transporter expression is associated with improved recovery of postischemic myocardial function.

Objective: Glucose is an important substrate for energy production in the developing heart. Increased glucose uptake rate and metabolism during ischemia and reperfusion are closely linked to postischemic myocardial recovery. The initial rate-limiting step for glycolysis is the transport of glucose across the plasma membrane by glucose transporters (GLUT-1 and GLUT-4).

Dopamine treatment of postischemic contractile dysfunction rapidly induces calcium-dependent pro-apoptotic signaling.

Background: Ischemia and adrenergic stimulation of cardiomyocyte cultures have been shown to induce apoptotic cell death. We hypothesized that in a model of contractile dysfunction following ischemia, a commonly used catecholamine such as dopamine augments cardiomyocyte apoptosis via activation of calcium-dependent signaling cascades.

Methods And Results: Isolated perfused rabbit hearts were subjected to 45 minutes of normothermic ischemia with cardioplegic arrest.

Protective effects of protein kinase C during myocardial ischemia require activation of phosphatidyl-inositol specific phospholipase C.

Background: Protein kinase C (PKC) activation during myocardial ischemia is thought to be cardioprotective. However, the mechanism of ischemia-induced PKC activation remains unclear. We hypothesized that ischemic PKC activation occurs through activation of phosphatidyl-inositol specific phospholipase C (PI-PLC) and protects the heart from ischemic injury.