Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion.

Abstract

Intermittent hypobaric hypoxia (IHH) protects hearts against ischemia-reperfusion (I/R) injury, but the underlying mechanisms are far from clear. ROS are paradoxically regarded as a major cause of myocardial I/R injury and a trigger of cardioprotection. In the present study, we investigated whether the ROS generated during early reperfusion contribute to IHH-induced cardioprotection. Using isolated perfused rat hearts, we found that IHH significantly improved the postischemic recovery of left ventricular (LV) contractile function with a concurrent reduction of lactate dehydrogenase release and myocardial infarct size (20.5 ± 5.3% in IHH vs. 42.1 ± 3.8% in the normoxic control, P < 0.01) after I/R. Meanwhile, IHH enhanced the production of protein carbonyls and malondialdehyde, respective products of protein oxidation and lipid peroxidation, in the reperfused myocardium and ROS generation in reperfused cardiomyocytes. Such effects were blocked by the mitochondrial ATP-sensitive K(+) channel inhibitor 5-hydroxydecanoate. Moreover, the IHH-improved postischemic LV performance, enhanced phosphorylation of PKB (Akt), PKC-ε, and glycogen synthase kinase-3β, as well as translocation of PKC-ε were not affected by applying H(2)O(2) (20 μmol/l) during early reperfusion but were abolished by the ROS scavengers N-(2-mercaptopropionyl)glycine (MPG) and manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin. Furthermore, IHH-reduced lactate dehydrogenase release and infarct size were reversed by MPG. Consistently, inhibition of Akt with wortmannin and PKC-ε with εV1-2 abrogated the IHH-improved postischemic LV performance. These findings suggest that IHH-induced cardioprotection depends on elevated ROS production during early reperfusion.

• Authors: Zhi-Hua Wang, Yi-Xiong Chen, Cai-Mei Zhang, Lan Wu, Zhuo Yu, Xiao-Long Cai, Yi Guan, Zhao-Nian Zhou, Huang-Tian Yang
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 301 Issue 4 Pg. H1695-705 (Oct 2011) ISSN: 1522-1539 [Electronic] United States
• PMID: 21821784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• KATP Channels
• Reactive Oxygen Species
• Cystine
• L-Lactate Dehydrogenase
• Prkce protein, rat
• Oncogene Protein v-akt
• Protein Kinase C-epsilon
• N-monoacetylcystine

Topics

• Air Pressure
• Animals
• Antioxidants (pharmacology)
• Cell Survival (physiology)
• Cystine (analogs & derivatives, pharmacology)
• Enzyme Activation (physiology)
• Hypoxia (physiopathology)
• KATP Channels (metabolism)
• L-Lactate Dehydrogenase (metabolism)
• Lipid Peroxidation
• Male
• Mitochondria, Heart (metabolism, physiology)
• Myocardial Contraction (physiology)
• Myocardial Infarction (pathology)
• Myocardial Ischemia (physiopathology)
• Myocardial Reperfusion
• Myocardial Reperfusion Injury (prevention & control)
• Myocytes, Cardiac (physiology)
• Oncogene Protein v-akt (metabolism, physiology)
• Oxidation-Reduction
• Protein Kinase C-epsilon (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Recovery of Function
• Signal Transduction (physiology)