Chronic intermittent hypoxia affects the cytosolic phospholipase A2α/cyclooxygenase 2 pathway via ß2-adrenoceptor-mediated ERK/p38 stimulation.

Cardiac resistance against acute ischemia/reperfusion (I/R) injury can be enhanced by adaptation to chronic intermittent hypoxia (CIH), but the changes at the molecular level associated with this adaptation are still not fully explored. Phospholipase A2 (PLA2) plays an important role in phospholipid metabolism and may contribute to membrane destruction under conditions of energy deprivation during I/R. The aim of this study was to determine the effect of CIH (7000 m, 8 h/day, 5 weeks) on the expression of cytosolic PLA2α (cPLA2α) and its phosphorylated form (p-cPLA2α), as well as other related signaling proteins in the left ventricular myocardium of adult male Wistar rats. Adaptation to CIH increased the total content of cPLA2α by 14 % in myocardial homogenate, and enhanced the association of p-cPLA2α with the nuclear membrane by 85 %. The total number of ß-adrenoceptors (ß-ARs) did not change but the ß2/ß1 ratio markedly increased due to the elevation of ß2-ARs and drop in ß1-ARs. In parallel, the amount of adenylyl cyclase decreased by 49 % and Giα proteins increased by about 50 %. Besides that, cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) increased by 36 and 84 %, respectively. In parallel, we detected increased phosphorylation of protein kinase Cα, ERK1/2 and p38 (by 12, 48 and 19 %, respectively). These data suggest that adaptive changes induced in the myocardium by CIH may include activation of cPLA2α and COX-2 via ß2-AR/Gi-mediated stimulation of the ERK/p38 pathway.

ß-Adrenergic signaling in rat heart is similarly affected by continuous and intermittent normobaric hypoxia.

Chronic hypoxia may produce a cardioprotective phenotype characterized by increased resistance to ischemia-reperfusion injury. Nevertheless, the molecular basis of cardioprotective effects of hypoxia is still not quite clear. The present study investigated the consequences of a 3-week adaptation to cardioprotective (CNH, continuous normobaric hypoxia) and nonprotective (INH, intermittent normobaric hypoxia; 23 h/day hypoxia followed by 1 h/day reoxygenation) regimen of hypoxia on ß-adrenergic signaling in the rat myocardium. Both regimens of hypoxia lowered body weight and led to marked right ventricular (RV) hypertrophy, which was accompanied by 25% loss of ß1-adrenergic receptors (ß1-ARs) in the RV. No significant changes were found in ß-ARs in left ventricular (LV) preparations from animals adapted to hypoxia. Although adenylyl cyclase (AC) activity stimulated through the G proteins was decreased in the RV and increased in the LV after exposure to hypoxia, there were no significant changes in the expression of the dominant myocardial AC 5/6 isoforms and the stimulatory G proteins. These data suggest that chronic normobaric hypoxia may strongly affect myocardial ß-adrenergic signaling but adaptation to cardioprotective and nonprotective regimens of hypoxia does not cause notably diverse changes.

ß-Adrenergic signaling, monoamine oxidase A and antioxidant defence in the myocardium of SHR and SHR-mtBN conplastic rat strains: the effect of chronic hypoxia.

The ß-adrenergic signaling pathways and antioxidant defence mechanisms play important roles in maintaining proper heart function. Here, we examined the effect of chronic normobaric hypoxia (CNH, 10% O2, 3 weeks) on myocardial ß-adrenergic signaling and selected components of the antioxidant system in spontaneously hypertensive rats (SHR) and in a conplastic SHR-mtBN strain characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischemia-resistant Brown Norway strain. Our investigations revealed some intriguing differences between the two strains at the level of ß-adrenergic receptors (ß-ARs), activity of adenylyl cyclase (AC) and monoamine oxidase A (MAO-A), as well as distinct changes after CNH exposure. The ß2-AR/ß1-AR ratio was significantly higher in SHR-mtBN than in SHR, apparently due to increased expression of ß2-ARs. Adaptation to hypoxia elevated ß2-ARs in SHR and decreased the total number of ß-ARs in SHR-mtBN. In parallel, the ability of isoprenaline to stimulate AC activity was found to be higher in SHR-mtBN than that in SHR. Interestingly, the activity of MAO-A was notably lower in SHR-mtBN than in SHR, and it was markedly elevated in both strains after exposure to hypoxia. In addition to that, CNH markedly enhanced the expression of catalase and aldehyde dehydrogenase-2 in both strains, and decreased the expression of Cu/Zn superoxide dismutase in SHR. Adaptation to CNH intensified oxidative stress to a similar extent in both strains and elevated the IL-10/TNF-α ratio in SHR-mtBN only. These data indicate that alterations in the mitochondrial genome can result in peculiar changes in myocardial ß-adrenergic signaling, MAO-A activity and antioxidant defence and may, thus, affect the adaptive responses to hypoxia.

Circadian Dexras1 in rats: Development, location and responsiveness to light.

Dexras1 has been shown to exhibit clock-dependent rhythm in mice suprachiasmatic nucleus (SCN), and its genetic deletion modulates circadian responses to photic and nonphotic cues. We show that the rhythmic expression of Dexras1 mRNA and protein in rat SCN already oscillates with low amplitude at postnatal day 3 and can be detected as early as embryonic day 20. In contrast, its expression in peripheral tissues is not rhythmic in adult rats either. The Dexras1 protein is expressed predominantly in the dorsomedial part of the SCN and the light pulse has only a limited effect on its expression. Our data provide the descriptive basis for speculation about the Dexras1 involvement in the rat circadian physiology.

Adenylyl cyclase signaling in the developing chick heart: the deranging effect of antiarrhythmic drugs.

The adenylyl cyclase (AC) signaling system plays a crucial role in the regulation of cardiac contractility. Here we analyzed the key components of myocardial AC signaling in the developing chick embryo and assessed the impact of selected ß-blocking agents on this system. Application of metoprolol and carvedilol, two commonly used ß-blockers, at embryonic day (ED) 8 significantly downregulated (by about 40%) expression levels of AC5, the dominant cardiac AC isoform, and the amount of Gsα protein at ED9. Activity of AC stimulated by forskolin was also significantly reduced under these conditions. Interestingly, when administered at ED4, these drugs did not produce such profound changes in the myocardial AC signaling system, except for markedly increased expression of Giα protein. These data indicate that ß-blocking agents can strongly derange AC signaling during the first half of embryonic heart development.