Intracellular Kinase Mechanism of the Cytoprotective Action of Adaptation to Chronic Hypoxia in Anoxia/Reoxygenation of
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Bulletin of Experimental Biology and Medicine, Vol. 169, No. 4, August, 2020 GENERAL PATHOLOGY AND PATHOPHYSIOLOGY
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Intracellular Kinase Mechanism of the Cytoprotective Action of Adaptation to Chronic Hypoxia in Anoxia/Reoxygenation of Cardiomyocytes N. V. Naryzhnaya, E. S. Prokudina, and A. S. Skryabina
Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 169, No. 4, pp. 426-430, April, 2020 Original article submitted May 28, 2019 On the model of anoxia/reoxygenation of isolated cardiomyocytes, we studied the role of kinases in the implementation of the cytoprotective effect of chronic continuous normobaric hypoxia (21 days on continuous exposure of rats at 12% O2). Anoxia/reoxygenation of cardiomyocytes from intact rats caused death of 16.5% cells, which was accompanied by the release of lactate dehydrogenase; in suspension of cardiomyocytes from adapted rats, only 6.8% cells died and the release of lactate dehydrogenase was lower by 60%. Incubation of cells with inhibitors of protein kinase C (chelerythrin, 10 mM), protein kinase Cδ (rottlerin, 1 μM), tyrosine kinases (genistein, 50 µM), but not with PI3K inhibitor (wortmannin, 100 nM) eliminated the cytoprotective effect of chronic continuous normobaric hypoxia. Thus, the cytoprotective effect of chronic normobaric hypoxia is realized through activation of protein kinase Cδ and tyrosine kinases, but not through PI3K. Key Words: cardiomyocytes; hypoxia; reoxygenation; adaptation; kinases Ischemic and reperfusion injuries underlie the pathogenesis of acute myocardial infarction and some other myocardial pathologies [3], therefore, the protection of cardiomyocytes from ischemia and reperfusion is an urgent problem of modern medicine. It is known that the myocardium of animals subjected to chronic hypoxia becomes resistant to the damaging during ischemia and reperfusion [6,7], however, the mechanisms of this effect remain little studied. It was found that the infarct-limiting, cardioprotective, and cytoprotective effects of chronic normobaric hypoxia are realized through activation of opioid receptors [4,6-8]. The cardioprotective effect of opioids is realized through activation of several intracellular kinases: protein kinases C, tyrosine kinases, and PI3K [3]. At the same time, intracellular mechanisms transmitting the protective signal from receptors to effector elements during adaptation to hypoxia remain unclear.
Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia. Address for correspondence: [email protected]. N. V. Naryzhnaya
The purpose of this study was to assess the involvement of protein kinase C, PI3K, cardiomyocyte tyrosine kinases in the cytoprotective effect of chronic normobaric hypoxia.
MATERIALS AND METHODS The experiments were performed on male Wistar rats (n=18) weighing 280-320 g. The animals were divided into two groups. Intact rats (n=8) were kept under standard vivarium conditions. The animals of the hypoxic group for 21 days were kept under condition
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