ANGIOTENSIN CONVERTING ENZYME 1 (ACE1) KNOCKDOWN IN THE MEDIAN PREOPTIC NUCLEUS (MNPO) ATTENUATES SUSTAINED DIURNAL HYPERTENSION FOLLOWING CHRONIC INTERMITTENT HYPOXIA

In order to study hypertension associated with Sleep Apnea, our lab uses a hypoxia model on rats. Rats are routinely used to model cardiovascular diseases of humans. We try to discover how the brain controls blood pressure in certain cardiovascular risk groups such as sleep apnea patients. This will help the scientific community better understand how sustained hypertension develops and progresses in sleep apnea patients and may lead to other discoveries about cardiovascular diseases. Purpose (a): Chronic Intermittent Hypoxia (CIH) is a model for the arterial hypoxemia seen in sleep apnea and is associated with a sustained increase in blood pressure throughout the diurnal cycle. Studies indicate that the MnPO contributes to this sustained component of CIH hypertension that persists during normoxia. MnPO neurons from rats show increased expression of the transcription factor FosB following CIH. Dominant-negative inhibition of a FosB splice variant in MnPO attenuates the sustained hypertension in CIH. We identified the pro-hypertensive ACE1 as a possible FosB target gene that may contribute to the sustained hypertension seen in CIH. Methods (b): We tested this hypothesis using a viral vector to knockdown ACE1 in the MnPO. Isoflurane anesthetized adult male rats were microinjected in the MnPO with 500nl of an adeno-associated virus containing GFP and either shRNA against ACE1 (shACE1) or a scrambled shRNA (shSCM). Changes in Mean arterial blood pressure (MAP) were recorded using radio telemetry. Rats were then exposed to CIH for 7 days through 3 minute periods of hypoxia (10% oxygen) and 3 minute periods of normoxia (21% oxygen) for 8 hours per day (0800-1600 h). Normoxic controls were exposed to room air. Laser capture microdissection followed by qRT-PCR showed that shACE1 significantly decreased ACE1 message in MnPO. Results (c): During CIH exposure, MAP significantly increased in both shACE1 and shSCM treated rats. During the normoxic dark phase, knockdown of ACE1 in the MnPO statistically decreased the sustained MAP component of CIH as compared to shSCM controls (P<0.001). Conclusions (d): These results show that ACE1 in the MnPO contributes to the sustained hypertension seen in our CIH model.