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

Adaptations to chronic hypoxia (CH) could reflect cellular changes within the cardiorespiratory regions of the rostral ventrolateral medulla (RVLM), the C1 region, and the pre-Bötzinger complex (pre-BötC). Previous studies have shown that the hypoxic chemosensitivity of these regions are heme oxygenase (HO) dependent and that CH induces HO-1. To determine the time course of HO-1 induction within these regions and explore its relevance to the respiratory and sympathetic responses during CH, the expression of HO-1 mRNA and protein in the RVLM and measures of respiration, sigh frequency, and sympathetic activity (spectral analysis of heart rate) were examined during 10 days of CH. Respiratory and sympathetic responses to acute hypoxia were obtained in chronically instrumented awake wild-type (WT) and HO-1 null mice. After 4 days of CH, there was a significant induction of HO-1 within the C1 region and pre-BötC. WT mice acclimated to CH by increasing peak diaphragm EMG after 10 days of CH but had no change in the respiratory response to acute hypoxia. There were no significant differences between WT and HO-1 null mice. In WT mice, hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity initially declined before returning toward baseline after 5 days of CH, correlating with the induction of HO-1. In contrast, HO-1 null mice had a persistent decline in hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity. We conclude that induction of HO-1 in these RVLM cardiorespiratory regions may be important for the hypoxic sensitivity of sighs and sympathetic activity during CH.