Abstract
Preconditioning is abolished in the prediabetic Zucker obese rat. It has been shown that prevention of mitochondrial permeability transition pore (mPTP) opening is involved in preconditioning by the noble gas helium. Here, we investigated: 1) whether helium induces pre- and postconditioning in Zucker rats and 2) whether possible regulators of the mPTP [i.e., mitochondrial respiration or the extracellular signal-regulated kinase (Erk) 1/2, Akt/glycogen synthase kinase (GSK)-3β signaling pathway] are influenced. Anesthetized Zucker lean (ZL) and Zucker obese (ZO) rats were randomized to seven groups. Control animals were not treated (ZL-/ZO-Con). Preconditioning groups (ZL-/ZO-He-PC) inhaled 70% helium for 3 × 5 or 6 × 5 min, and postconditioning groups (ZL-/ZO-He-PostC) inhaled 70% helium for 15 min at the onset of reperfusion. Animals underwent 25 min of ischemia and 120 min of reperfusion. In additional experiments, hearts were excised after the third helium exposure for analysis of mitochondrial respiration and for Western blot analysis of Erk1/2, Akt, and GSK-3β phosphorylation. Helium reduced infarct size from 52 ± 3% (mean ± S.E.) to 32 ± 2% and 37 ± 2% in ZL rats (ZL-HE-PC, ZL-He-PostC), respectively, but not in ZO rats [ZO-He-PC, 56 ± 3%; ZO-He-PC (6×), 57 ± 4%; and ZO-He-PostC, 51 ± 3% versus ZO-Con, 54 ± 3%]. Mitochondrial respiration analysis showed that helium causes mild uncoupling in ZL rats (2.27 ± 0.03 versus 2.51 ± 0.03) but not in ZO rats (2.52 ± 0.04 versus 2.52 ± 0.03). Helium had no effect on Erk1/2 and Akt phosphorylation. GSK-3β phosphorylation during ischemia was reduced after helium application in ZL but not in ZO rats. Helium-induced preconditioning is abolished in obese Zucker rats in vivo, probably caused by a diminished effect of helium on mitochondrial respiration.
Footnotes
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This work was supported by the Netherlands Organization for Health Research and Development (ZonMw) [MD-Medical Research Trainee (AGIKO) Grant 92003450] (Den Haag, The Netherlands).
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R.H. and A.H. contributed equally to this work.
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doi:10.1124/jpet.108.149971.
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ABBREVIATIONS: mKATP, mitochondrial ATP-activated potassium; mPTP, mitochondrial permeability transition pore; GSK, glycogen synthase kinase; ZL, Zucker lean; ZO, Zucker obese; Con, control; He-PC, helium preconditioning; Erk, extracellular signal-regulated kinase; RCI, respiratory control index; mKCa, mitochondrial calcium-sensitive potassium channel; NS1619, 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one.
- Received December 17, 2008.
- Accepted February 24, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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