Acute intermittent hypoxia activates myocardial cell survival signaling

Abstract

Intermittent hypoxia (IH) with repeated episodes of hypoxia-normoxia cycle has been shown to exert preconditioning-like cardioprotective effects. To understand the mechanism of these events, we investigated the changes in cardiac gene expression in response to acute IH. Mice were subjected to five cycles of 2 min of 10% O(2) plus 2 min of 21% O(2). RNA was isolated, and gene array analysis was performed. Results show that the expression of antiapoptotic genes, such as Bcl-2 and Bcl-x(L), were increased after acute IH. GATA-4 regulates transcription of these genes, and, consistently, GATA-4 activity was increased by acute IH. Although the phosphorylation of GATA-4 has been shown to regulate its activity, no changes in GATA-4 phosphorylation status by acute IH were noted. Gene transcription of gata4 was increased by acute IH, and this might be responsible for the enhanced GATA activity. To understand the mechanism of acute IH activation of gata4 gene transcription, we identified a promoter region of the mouse gata4 gene that is 1,000 bp immediately upstream from the transcriptional start site. In cardiac muscle cells, truncation of 1,000 to 250 bp did not alter the transcriptional activity, suggesting that the proximal 250-bp region contains important transcriptional regulatory sites. We further found that acute IH activates factors which bind to the proximal 100-bp region. Thus acute IH activates not yet identified factors that bind to the proximal 100-bp region of the gata4 promoter and, in turn, increases gata4 gene transcription, leading to enhanced expression of Bcl-2 and Bcl-x(L).

Capillary Supply and Fiber Morphometry in Rat Myocardium after Intermittent Exposure to Hypobaric Hypoxia

“…These cells induce specific genes involved in oxygen homeostasis after the mediation of hypoxia-inducible factor (HIF-1␣), in turn upregulating vascular endothelial growth factor (VEGF), which are strongly activated after intermittent hypoxia (Yuan et al, 2005). Consistent with the results of other studies that used distinct protocols of intermittent hypoxia (Tin'kov and Aksenov, 2002;Park et al, 2007), our findings support the clinical use of IHH for myocardial recovery, since this protocol improves oxygen delivery to myocardium fibers. Our results give support to previous reports by E. Marticorena, in Peru, who originally described a procedure for cardiac recovery.…”

GATA-4 Transcription Factor Regulates Cardiac COX-2 Expression Induced by Nicorandil in Left Ventricle of Rats

“…With respect to cellular signaling pathways, a recent report demonstrated that GATA-4-regulated microRNAs confer a cardiomyocyte-protective effect accompanied by activation of COX-2-prostaglandin signaling pathways [24]. An earlier report demonstrated that GATA-4 mRNA and activity in the hearts of mice were increased from 0.5 h after IPC [25]; in that study, the time course of GATA-4 expression was comparable to that in this study. Taken together, these data suggest that induction of GATA-4 by nicorandil would be a first step in the induction of COX-2 in the left ventricle.…”

Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link

“…While treatment with acute IH exerted cardioprotective effects, treating mice with a prolonged period of IH induced increased susceptibility of the heart, which was mediated by increased oxidative stress. Additional treatment with prolonged IH reversed the added myocardial damage [113,114]. It is therefore of utmost importance to delineate the complex effects of IH on the GATA family of transcription factors in the human heart.…”