Gene expression and phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia

Physiol Genomics. 2005 Aug 11;22(3):292-307. doi: 10.1152/physiolgenomics.00217.2004. Epub 2005 May 31.


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. Molecular mechanisms underlying these cardiac alterations are not well understood. We hypothesized that 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 changes in gene expression in the 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 one hand, upregulation in RNA and protein levels of eukaryotic translation initiation factor-2alpha and -4E (eIF-2alpha and eIF-4E) was found in CCH, whereas eIF-4E was downregulated in 1- and 2-wk 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 downregulation of heart development-related genes (e.g., notch gene homolog-1, MAD homolog-4) and the upregulation of proteolysis genes (e.g., calpain-5) in the CIH heart can explain the lack of hypertrophy in CIH. Interestingly, apoptosis was enhanced in CCH but not CIH, and this was correlated with an upregulation of proapoptotic genes and downregulation of anti-apoptotic genes in CCH. In summary, our results indicate that 1) the pattern of gene response to CCH is different from that of CIH in mouse heart, and 2) the identified expression differences in certain gene groups are helpful in dissecting mechanisms responsible for phenotypes observed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Body Weight
  • DNA, Complementary / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Eukaryotic Initiation Factor-2 / biosynthesis
  • Eukaryotic Initiation Factor-4E / biosynthesis
  • Gene Expression Regulation*
  • Heart
  • Hematocrit
  • Hypertrophy
  • Hypoxia*
  • In Situ Nick-End Labeling
  • Mice
  • Microscopy
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Nucleic Acid Hybridization
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Temperature
  • Up-Regulation


  • DNA, Complementary
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factor-4E
  • RNA, Messenger