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

Abstract

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.