Abstract 13100: Genetic Ablation of Astrocyte-specific Angiotensin II Type 1 Receptors Improves Prognosis of Myocardial Infarction-Induced Heart Failure
Introduction: Abnormal sympathoexcitation worsens the prognosis of myocardial infarction (MI)-induced heart failure. We and other investigators revealed that activated brain angiotensin II type 1 receptors (AT1R) cause sympathoexcitation via oxidative stress. Previous reports, however, focused on neuronal AT1R despite the greater abundance of astrocytes than neurons in the brain, because normal astrocytes have few AT1R. Several very recent reports demonstrated that astrocytes are involved in the pathophysiology of MI-induced heart failure, but it remains unknown whether AT1R activation in the neurons or astrocytes is more crucial in MI-induced heart failure. We investigated the hypothesis that astrocytic AT1R activation plays a key role in the prognosis and left ventricular (LV) remodeling of MI-induced heart failure by genetic ablation of astrocyte-specific AT1R.
Methods and Results: Using the Cre-LoxP system, we generated astrocyte-specific AT1R knockout mice (CKO-mice). At 30 days after MI, LV size and heart weight of CKO-mice were significantly smaller than those of control-MI mice (LV end-diastolic/systolic dimension: 5.0±0.1/4.5±0.1 vs. 6.1±0.1/5.6±0.1 mm, n=6, p<0.01). Urine norepinephrine excretion for 24 hours, as an indicator of sympathoexcitation, was significantly lower in CKO-MI mice than in control-MI mice (0.43±0.03 vs. 0.56±0.02μg/day, n=8-9, p<0.05). Expressions of AT1R protein and mRNA in the brainstem of CKO-MI mice were not increased compared to CKO-sham mice (relative expression; protein: 0.34±0.04 vs. 0.31±0.05; mRNA: 0.52±0.05 vs. 0.50±0.10, n=5-6), although they were significantly higher in control-MI mice than in control-sham mice (relative expression; protein: 0.61±0.03 vs. 0.30±0.05; mRNA: 0.96±0.08 vs. 0.45±0.02, n=5-6, p<0.01). Survival rate at 30 days after MI was significantly improved in CKO-MI mice compared to control-MI mice (90 vs. 63 %, n=20-22, p<0.05).
Conclusions: Genetic ablation of astrocytic AT1R significantly improved survival prevented LV remodeling and sympathoexcitation in MI-induced heart failure. These findings indicate that astrocytic AT1R, not neuronal AT1R, have a key role in the pathophysiology of MI-induced heart failure.
Author Disclosures: K. Isegawa: None. Y. Hirooka: None. T. Kishi: None. K. Sunagawa: None.
- © 2014 by American Heart Association, Inc.