The Role of Angiotensin Converting Enzyme 1 within the Median Preoptic Nucleus Following Chronic Intermittent Hypoxia

These experiments focused on the importance of the brain renin-angiotensin system (RAS) in hypertension caused by a chronic intermittent hypoxia (CIH) model of the hypoxemia associated with sleep apnea. In the CIH model, the sustained diurnal blood pressure increase has been shown to be dependent on the transcription factor FosB and its downstream target genes such as angiotensin converting enzyme 1 (ACE1) in the median preoptic nucleus (MnPO) in the anterior hypothalamus. These studies focused on the transcriptional regulation of MnPO ACE1 and the development of the sustained CIH hypertension. The first project focused on ACE1 within the MnPO and its regulation by FosB during CIH. Using immunohistochemistry, ACE1 staining within the MnPO did not overlap with glial fibrillary acidic protein (GFAP), a glial cell marker. ACE1 and FosB colocalization increased within the MnPO following 7 days of CIH. A retrograde tract tracer, fluorogold, was used to determine if ACE1 positive MnPO neurons project to the paraventricular nucleus of the hypothalamus (PVN). MnPO cells containing ACE1 and FosB immunoreactivity after CIH did project to the PVN, an area known to regulate sympathetic nerve activity. Chromatin Immunoprecipitation Assay was used to authenticate an association of FosB with ACE1 within the MnPO following CIH. In the MnPO, the association of FosB with the ACE1 gene was significantly increased by CIH. The second aim tested the functional role of MnPO ACE1 in sustained diurnal CIH hypertension. We used virally mediated expression of short hairpin RNA (shRNA) against ACE1 to significantly knockdown MnPO ACE1. Rats injected in the MnPO with shRNA against ACE1 demonstrated normal blood pressure responses to hypoxic events but the sustained blood pressure increase to CIH was significantly attenuated. ACE1 knockdown within the MnPO also decreased FosB/ΔFosB staining within the MnPO, the PVN and the rostral ventrolateral medulla (RVLM) but not in the nucleus of the solitary tract. Together, these studies suggest that MnPO ACE1 contributes to the development of sustained CIH hypertension.