Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic intermittent hypoxia in mice

Chronic intermittent hypoxia (CIH) increases sympathetic tone and respiratory instability. Our previous work showed that chronic hypoxia induces the oxygen-sensing enzyme heme oxygenase-1 (HO-1) within the C1 sympathoexcitatory region and the pre-Bötzinger complex (pre-BötC). We therefore examined the effect of CIH on time course of induced expression of HO-1 within these regions and determined whether the induction of HO-1 correlated with changes in respiratory, sigh frequency, and sympathetic responses (spectral analysis of heart rate) to acute hypoxia (10% O₂) during 10 days of exposure to CIH in chronically instrumented awake wild-type (WT) and HO-1 null mice (HO-1^–/–). HO-1 was induced within the C1 and pre-BötC regions after 1 day of CIH. There were no significant differences in the baseline respiratory parameters between WT and HO-1^–/–. Prior to CIH, acute hypoxia increased respiratory frequency in both WT and HO-1^–/–; however, minute diaphragm electromyogram activity increased in WT but not HO-1^–/–. The hypoxic respiratory response after 1 and 10 days of CIH was restored in HO-1^–/–. CIH resulted in an initial significant decline in 1) the hypoxic sigh frequency response, which was restored in WT but not HO-1^–/–, and 2) the baseline sympathetic activity in WT and HO-1^–/–, which remained stable subsequently in WT but not in HO-1^–/–. We conclude that 1) CIH induces expression of HO-1 in the C1 and pre-BötC regions within 1 day and 2) HO-1 is necessary for hypoxia respiratory response and contributes to the maintenance of the hypoxic sigh responses and baseline sympathetic activity during CIH.

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