Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury.
AM J PHYSIOL-HEART C
H2123 - H2134.
Paiva MA, Rutter-Locher Z, Goncalves LM, Providencia LA, Davidson SM, Yellon DM, Mocanu MM. Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury. Am J Physiol Heart Circ Physiol 300: H2123-H2134, 2011. First published March 18, 2011; doi: 10.1152/ajpheart.00707.2010.-AMPK activation during ischemia helps the myocardium to cope with the deficit of energy production. As AMPK activity is considered to be impaired in diabetes, we hypothesized that enhancing AMPK activation during ischemia above physiological levels would protect the ischemic diabetic heart through AMPK activation and subsequent inhibition of mitochondrial permeability transition pore (mPTP) opening. Isolated perfused hearts from normoglycemic Wistar or diabetic Goto-Kakizaki (GK) rats (n >= 6/group) were subjected to 35 min of ischemia in the presence of 10, 20, and 40 mu M of A-769662, a known activator of AMPK, followed by 120 min of reperfusion with normal buffer. Myocardial infarction and AMPK phosphorylation were assessed. The effect of A-769662 on mPTP opening in adult cardiomyocytes isolated from both strains was also determined. A-769662 at 20 mu M reduced infarct size in both Wistar (30.5 +/- 2.7 vs. 51.8 +/- 3.9% vehicle; P < 0.001) and GK hearts (22.7 +/- 3.0 vs. 48.5 +/- 4.7% vehicle; P < 0.001). This protection was accompanied by a significant increase in AMPK and GSK-3 beta phosphorylation. In addition, A-769662 significantly inhibited mPTP opening in both Wistar and GK cardiomyocytes subjected to oxidative stress. We demonstrate that AMPK activation during ischemia via A-769662 reduces myocardial infarct size in both the nondiabetic and diabetic rat heart. Furthermore, this cardioprotective effect appears to be mediated through inhibition of mPTP opening. Our findings suggest that improving AMPK activation during ischemia can be another mechanism for protecting the ischemic heart.
|Title:||Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury|
|Keywords:||diabetes, signal transduction, MITOCHONDRIAL PERMEABILITY TRANSITION, MYOCARDIAL-INFARCTION, CARDIAC MYOCYTES, OXIDATIVE STRESS, NAD(P)H OXIDASE, KINASE CASCADE, GLUCOSE-UPTAKE, FLOW ISCHEMIA, IN-VIVO, INHIBITION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science|
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