Cardiac
fatty acid oxidation (FAO)
enzyme gene expression is known to be downregulated during
hypoxia in concordance with reduced FAO rates. To evaluate this metabolic switch, the transcriptional control of a cardiac FAO
enzyme-encoding gene (
medium-chain acyl-CoA dehydrogenase, MCAD) was characterized in response to hypobaric
hypoxia. Transgenic mice harboring 560-bp of the human MCAD gene promoter fused to the bacterial
chloramphenicol acetyl
transferase (CAT) reporter gene were exposed to moderate (14% O2) or severe (8% O2)
hypoxia for 2 or 7 days. MCAD-CAT activity and gene expression were significantly downregulated following 7 days of moderate
hypoxia versus normoxic controls (p < 0.05). In parallel two known transcriptional regulators of MCAD expression,
PPARalpha and Sp3, were concordantly downregulated at 7 days
hypoxia. In contrast, severe
hypoxia increased MCAD-CAT activity by 31 +/- 1.4% after 2 days
hypoxia, returning to base +/- 4% after 2 days (p < 0.001) and returned to control levels after 7 days of
hypoxia. These data demonstrate that MCAD gene expression is downregulated after 7 days of moderate
hypoxia and inversely regulated with severe
hypoxia. The known MCAD transcriptional regulators
PPARalpha and Sp3 mirror MCAD expression. These data indicate that the transcriptional regulatory circuits involved in the control of MCAD gene expression under hypoxic conditions are modulated by upstream factors that are sensitive to the levels of
oxygen.