Isegawa Kengo, Hirooka Yoshitaka, Katsuki Masato, Kishi Takuya, Sunagawa Kenji
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan;
Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and
Am J Physiol Heart Circ Physiol. 2014 Nov 15;307(10):H1448-55. doi: 10.1152/ajpheart.00462.2014. Epub 2014 Sep 12.
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.
增强的中枢交感神经输出会恶化心肌梗死（MI）后心力衰竭患者的左心室（LV）重塑和预后。先前的研究表明，脑干中脑源性血管紧张素II 1型受体（AT₁R）的激活由于神经元AT₁R上调而导致交感神经兴奋。然而，最近的研究揭示了星形胶质细胞在调节神经元活动中的重要性，但星形胶质细胞的变化是否会影响心力衰竭时的中枢交感神经输出尚不清楚。在正常状态下，AT₁R在星形胶质细胞中仅微弱表达。我们假设，心力衰竭时星形胶质细胞中的AT₁R上调，并调节相邻神经元的活动，导致交感神经输出增强。在本研究中，通过靶向删除星形胶质细胞特异性AT₁R，我们研究了星形胶质细胞中的AT₁R在增强中枢交感神经输出中是否起关键作用，从而影响LV重塑过程和MI诱导的心力衰竭的预后。使用Cre-LoxP系统，我们生成了胶质纤维酸性蛋白（GFAP）特异性AT₁R基因敲除（GFAP/AT₁RKO）小鼠。作为交感神经兴奋指标的24小时尿去甲肾上腺素排泄量，GFAP/AT₁RKO-MI小鼠明显低于对照-MI小鼠。MI后GFAP/AT₁RKO小鼠的LV大小和心脏重量明显小于对照小鼠。与对照-MI小鼠相比，GFAP/AT₁RKO-MI小鼠的预后明显改善。我们的研究结果表明MI诱导的心力衰竭中脑干星形胶质细胞中AT₁R表达上调，通过交感神经兴奋恶化LV重塑和预后。因此，除了神经元AT₁R外，星形胶质细胞中的AT₁R似乎在增强心力衰竭时的中枢交感神经输出中起关键作用。
