Abstract 19713: Decreased Astrocytes via Central Angiotensin II Receptor and Dysfunction of Nrf2 is Associated With Sympathoexcitation in Heart Failure

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Abstract

Introduction: We have determined that central angiotensin II receptor (AT1R)-induced oxidative stress causes sympathoexcitation heart failure. Interestingly, our recent study showed that astrocyte, not neuron, -specific deletion of AT1R caused prominent sympathoinhibition in myocardial infarction (MI)-induced heart failure rats. However, the precise mechanism by which central AT1R causes dysfunction of astrocyte in heart failure has not been fully clarified. We hypothesized that decreased astrocytes caused by central AT1R-induced oxidative stress and dysfunction of antioxidant cytoprotective transcription factor (nuclear factor erythroid 2-related factor 2; Nrf2) is associated with sympathoexcitation in MI-induced heart failure by coronary ligation.

Methods and Results: Expression of glial fibrillary acidic protein (GFAP; cytoskeletal protein of astrocyte) and Nrf2 in the vasomotor center were significantly lower in MI-induced heart failure than in sham rats. MI-induced heart failure treated with intracerebroventricular infusion (ICV) of AT1R blocker for 14 days had significantly higher GFAP (2.1±0.2 vs. 1.1±0.1 unit, n=5, p<0.05) and lower oxidative stress (0.9±0.1 vs. 1.4±0.2 μmol/g wet wt, n=5, p<0.05) in the vasomotor center with sympathoinhibition (24 hours urinary norepinephrine excretion, 1.2±0.2 vs. 1.5±0.1 μg /day, n=5, p<0.05) compared to that treated with vehicle. However, Nrf2 in the vasomotor center did not altered among ARB and vehicle group. Additive oral administration of Nrf2 activator, dimethyl fumarate, with ICV of AT1R blocker for 14 days had additionally sympathoinhibition (0.9±0.1 vs. 1.2±0.2 μg /day, n=5, p<0.05) at normal levels with significantly lower oxidative stress (0.6±0.2 vs. 0.9±0.1 μmol/g wet wt, n=5, p<0.05) and higher GFAP (2.7±0.1 vs. 2.1±0.2 unit, n=5, p<0.05) in the vasomotor center. As a result, ICV of AT1R blocker with oral administration of Nrf2 activator for 14 days successfully reduced left ventricular end-diastolic pressure to almost normal level compared to vehicle (4±1 vs. 11±2 mmHg, n=5, p<0.05)

Conclusions: Decreased astrocytes via central AT1R-induced oxidative stress and dysfunction of Nrf2 is associated with sympathoexcitation in MI-induced heart failure rats.

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