title: Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure.
abstract: 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 (AT₁R) in the brain stem leads to sympathoexcitation due to neuronal AT₁R 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 AT₁R, 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/AT₁RKO) mice. Urinary norepinephrine excretion for 24 h, as an indicator of sympathoexcitation, was significantly lower in GFAP/AT₁RKO-MI mice than in control-MI mice. LV size and heart weight after MI were significantly smaller in GFAP/AT₁RKO mice than in control mice. Prognosis was significantly improved in GFAP/AT₁RKO-MI mice compared with control-MI mice. Our findings indicated that AT₁R 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 AT₁R, AT₁R in astrocytes appear to have a key role in enhancing central sympathetic outflow in heart failure.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan;
authors.forename: Kengo
authors.initials: K
authors.lastname: Isegawa
authors.affiliation: Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and hyoshi@cardiol.med.kyushu-u.ac.jp.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan;
authors.forename: Masato
authors.initials: M
authors.lastname: Katsuki
authors.affiliation: Department of Advanced Therapeutics for Cardiovascular Diseases, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kishi
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan;
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015415:Biomarkers / Q000652:urine; D001933:Brain Stem / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000652:urine; D011401:Promoter Regions, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013318:Stroke Volume; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C544066:Agtr1a protein, mouse; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D044140:Receptor, Angiotensin, Type 1; D009638:Norepinephrine
keywords: angiotensin II type 1 receptor; astrocyte; heart failure; sympathetic nervous system