Isegawa K, Hirooka Y, Katsuki M, Kishi T, Sunagawa K. Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure. Am J Physiol Heart Circ Physiol 307: H1448 -H1455, 2014. First published September 12, 2014 doi:10.1152/ajpheart.00462.2014.-Enhanced central sympathetic outflow worsens left ventricular (LV) remodeling and prognosis in heart failure after myocardial infarction (MI). Previous studies suggested that activation of brain angiotensin II type 1 receptors (AT 1R) in the brain stem leads to sympathoexcitation due to neuronal AT 1R upregulation. Recent studies, however, revealed the importance of astrocytes for modulating neuronal activity, but whether changes in astrocytes influence central sympathetic outflow in heart failure is unknown. In the normal state, AT1R are only weakly expressed in astrocytes. We hypothesized that AT1R in astrocytes are upregulated in heart failure and modulate the activity of adjacent neurons, leading to enhanced sympathetic outflow. In the present study, by targeting deletion of astrocyte-specific AT 1R, we investigated whether AT1R in astrocytes have a key role in enhancing central sympathetic outflow, and thereby influencing LV remodeling process and the prognosis of MI-induced heart failure. Using the Cre-LoxP system, we generated glial fibrillary acidic protein (GFAP)-specific AT1R knockout (GFAP/ AT 1RKO) mice. Urinary norepinephrine excretion for 24 h, as an indicator of sympathoexcitation, was significantly lower in GFAP/ AT 1RKO-MI mice than in control-MI mice. LV size and heart weight after MI were significantly smaller in GFAP/AT 1RKO mice than in control mice. Prognosis was significantly improved in GFAP/ AT 1RKO-MI mice compared with control-MI mice. Our findings indicated that AT 1R expression was upregulated in brain stem astrocytes in MI-induced heart failure, which worsened LV remodeling and prognosis via sympathoexcitation. Thus, in addition to neuronal AT 1R, AT1R in astrocytes appear to have a key role in enhancing central sympathetic outflow in heart failure.astrocyte; angiotensin II type 1 receptor; sympathetic nervous system; heart failure ENHANCED central sympathetic outflow is a cardinal manifestation of heart failure, which influences the left ventricular (LV) remodeling process and eventually worsens prognosis (10, 45). Activation of brain angiotensin II type 1 receptors (AT 1 R) enhances sympathetic outflow in experimental heart failure (12, 13, 30). Furthermore, activation of AT 1 R has a major role in the production of reactive oxygen species (ROS) in the brain stem and hypothalamus (5, 17). For example, ROS blockade in the central nervous system by intracerebroventricular injection of superoxide dismutase or tempol prevents sympathoexcitation after myocardial infarction (MI) (19). In particular, AT 1 Rinduced ROS production in the rostral ventrolateral medulla (RVLM) contributes to enhance the sympathetic outflow in heart failure (12, 13). Previou...