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1 Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
2 Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
3 Pharmaceutical Sciences, Idaho State University College of Pharmacy, Pocatello, ID, USA
* To whom correspondence should be addressed. E-mail: ghaddad{at}aecom.yu.edu.
Chronic constant hypoxia (CCH), such as in pulmonary diseases or high altitude, and chronic intermittent hypoxia (CIH), such as in sleep apnea, can lead to major changes in the heart. The molecular mechanisms underlying these cardiac alterations are not well understood. We hypothesized that the changes in gene expression could help to delineate such mechanisms. The current study used a neonatal mouse model in CCH or CIH combined with cDNA microarrays to determine the changes in gene expression in CCH or CIH mouse heart. Both CCH and CIH induced substantial alterations in gene expression. In addition, a robust right ventricular hypertrophy and cardiac enlargement was found in CCH, but not in CIH-treated mouse heart. On the one hand, up-regulation in RNA and protein levels of eukaryotic translation initiation factor 2
and 4E (eIF-2and eIF-4E) were found in CCH while eIF-4E was down regulated in 1 week and 2 weeks CIH suggesting that eIF-4E is likely to play an important role in the cardiac hypertrophy observed in CCH-treated mice. On the other hand, the specific down-regulation of heart development related genes (e.g., notch gene homolog 1, MAD homolog 4) and the up-regulation in proteolysis genes (e.g., calpain 5) in CIH heart can explain the lack of hypertrophy in CIH. Interestingly, apoptosis was enhanced in CCH but not in CIH, and this was correlated with an up-regulation of pro-apoptotic genes and down-regulation of anti-apoptotic genes in CCH. In summary, our results indicate that: a) the pattern of gene response to CCH is different from that of CIH in mouse heart, and b) the identified expression differences in certain gene groups are helpful in dissecting the mechanisms responsible for the phenotypes observed.
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