Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2

Abstract

. Intermittent hypoxia-induced delayed cardioprotection is mediated by PKC and triggered by p38 MAP kinase and Erk1/2.. Journal of Molecular and Cellular Cardiology, Elsevier, 2007, 42 (2) AbstractObjective. We previously reported that acute intermittent hypoxia (IH) confers delayed cardioprotection against a prolonged ischemic insult in the rat, via the involvement of nitric oxide synthase and K ATP channels. In the present study, we investigated the role of protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K), stress activated p38 MAP kinase (MAPK) and extracellular signal regulated kinase (ERK1/2) using selective inhibitors of these pathways. Methods. Adult male rats were exposed to 1-min cycles of IH (10% O 2 , 40 sec) / normoxia (21% O 2 , 20 sec) during 4 hrs or to normoxic cycles. 24 hrs later, isolated hearts were perfused in Langendorff mode and subjected to a 30-min global ischemia followed by 120 min of reperfusion. Results. Compared to normoxic conditions, IH significantly reduced infarct size (22.2  2.4% vs 33.8  2.6%, p<0.05), improved coronary flow and decreased the contracture at reperfusion. When administered before sustained ischemia, chelerythrine (a PKC inhibitor) abolished both the IH-induced reduction in infarct size (36.1  4.9%) and improvement in hemodynamic parameters. In contrast, chelerythrine administration 10 min before IH, did not modify the delayed cardioprotective response. Similarly, wortmannin (a PI3K inhibitor) administration 10 min before IH was unable to block the cardioprotective effects. However, administration of SB203580 (a p38 MAPK inhibitor) and PD98059 (an Erk1/2 inhibitor), 30 min before IH abolished its delayed infarct-sparing effect (32.2  3.4% and 33.9  2.9% respectively). In addition, 24 hrs after IH, a significant increase in p38 MAPK and Erk1/2 phosphorylation was observed by Western blot. Conclusion. These results suggest that the delayed preconditioning induced by intermittent hypoxia does not involve the PI3K signalling pathway and that is mediated by PKC and triggered by p38 MAPK and Erk1/2.

Hypoxia: The Force that Drives Chronic Kidney Disease

“…When this occurs, renal cells initially respond with protective mechanisms that center around the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 and the resulting stabilization of both HIF-1α and HIF-2α. [94][95][96]292,[323][324][325] These protective mechanisms include the up-regulation of pro-angiogenic factors such as isoform 164 of VEGF-A that protect against capillary rarefaction, and increased expression of matrix metalloproteinases that effect repair and protect against fibrosis by degrading extracellular matrix. 326,327 In addition, short-term exposure to hypoxia leads to increased renal expression of antioxidants such as nuclear factor erythroid 2-related factor 2, hemeoxygenase 1, and metallothionein I that protect against fibrosis and inflammation induced by reactive oxygen species.…”

Sleep apnoea and the heart

“…It has been suggested that alteration in long-term facilitation and hypoxic ventilatory response in reply to intermittent hypoxia exposure could lead to breathing stability and reduction in apnoea/hypopnoea index, although this is still conflicting [22]. There are also potential beneficial effects with regard to cardiovascular consequences that have been suggested in animals exposed to intermittent hypoxia [23][24][25]. This might also be the case in OSA with respect to vascular adaptations [26,27] and possibly lower mortality [16].…”

Chronic Intermittent Hypobaric Hypoxia Ameliorates Ischemia/Reperfusion-Induced Calcium Overload in Heart via Na+/Ca2+Exchanger in Developing Rats

“…Moderate chronic intermittent hypobaric hypoxia (CIHH), similar to ischemic preconditioning and long-term adaptation to high-altitude hypoxia, protects the heart against I/R injury [9,10,11,12]. This CIHH-induced cardiac protection persists longer than ischemic preconditioning [13,14] and is associated with less side effects on the body, such as polycythemia, right ventricular hypertrophy and pulmonary hypertension compared with long-term adaptation to high-altitude hypoxia [15,16,17].…”