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...
SummaryIn metabolic syndrome (MetS), previous studies have suggested that cognitive decline is worsened. Among the factors associated with cognition, decreased brain-derived neurotrophic factor (BDNF) in the hippocampus causes cognitive decline. We previously reported that exercise training with calorie restriction yielded protection against cognitive decline via BDNF in the hippocampus of hypertensive rats. The aim of the present study was to determine whether or not calorie restriction results in protection against cognitive decline via BDNF and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of MetS model rats. We divided dietary-induced obesity-prone and hypertensive rats (OP), as metabolic syndrome model rats, into three groups, fed with a high fat diet (HF), treated with calorie restriction (CR) plus vehicle, and treated with CR and ANA-12 (a TrkB antagonist) (CR+A). After treatment for 28 days, body weight, insulin, fasting blood glucose, adiponectin, systolic blood pressure, and oxidative stress in the hippocampus were significantly lower, and BDNF expression in the hippocampus was significantly higher in CR and CR+A than in HF. Cognitive performance determined by the Morris water maze test was significantly higher in CR than in HF, whereas the benefit was attenuated in CR+A. In conclusion, calorie restriction protects against cognitive decline via up-regulation of BDNF/TrkB through an antioxidant effect in the hippocampus of dietary-induced obesity rats. (Int Heart J 2015; 56: 110-115) Key words: Metabolic syndrome, Cognition O ne of the important types of organ damage in metabolic syndrome (MetS) is cognitive decline. 1) MetS-associated factors are linked to volume losses in the hippocampus, and MetS negatively impacts cognition by impaired vascular reactivity, neuro-inflammation, oxidative stress, and abnormal brain lipid metabolism.1) Among the factors associated with cognition, brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) are known to be involved in the protective mechanisms against stress and cell death as an antioxidant.2-6) Systemic oxidative stress and/or antioxidant deficiency cause cognitive decline, 7) and oxidative stress in the hippocampus in particular impairs cognitive function. 8) However, it has not been clarified whether BDNF/TrkB in the hippocampus of metabolic syndrome patients is impaired or not.Not only pharmacological therapy but also exercise training 9-11) and calorie restriction 12,13) have been suggested to protect against cognitive decline. The benefits of calorie restriction on metabolic syndrome have been already established via improvement of insulin-resistance. [13][14][15][16][17][18] However, in a previous clinical study, calorie restriction and/or exercise training did not protect against cognitive decline. 19) We previously demonstrated that exercise training plus calorie restriction causes synergistic protection against cognitive decline via up-regulation of BDNF in the hippocampus of stroke-pron...
Exercise training normalizes sympathetic outflow in hypertension and chronic heart failure. The aim of this study was to determine whether the exercise training inhibits sympathetic nerve activity (SNA) via reduction of oxidative stress through blocked angiotensin II type 1 receptor (AT(1)R) in rostral ventrolateral medulla (RVLM). We divided stroke-prone spontaneously hypertensive rats (SHRSP) into SHRSP with exercised training (SHRSP-EX) and control (SHRSP-C). SNA and oxidative stress in the RVLM were significantly lower in SHRSP-EX than in SHRSP-C. These results suggest that exercise training inhibits SNA via reduction of oxidative stress through blocked AT(1)R in the RVLM of hypertension.
Abnormal elevation of blood pressure in early morning (rest-to-active phase) is suggested to cause cardiovascular events. We investigated whether azilsartan (AZL), a novel potent angiotensin receptor blocker, suppresses blood pressure elevation from the light-rest to dark-active phase in spontaneously hypertensive rats (SHRs). AZL has a sustained depressor effect around the rest-to-active phase in SHRs to a greater extent than candesartan (CAN), despite their similar depressor effects for over 24 h. AZL did not cause sympathoexcitation. These results suggest that AZL has a more sustained depressor effect than CAN around the rest-to-active phase in SHRs, and might have advantages for early morning hypertension.
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