Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

Isegawa, Kengo; Hirooka, Yoshitaka; Katsuki, Masashi; Kishi, Takuya; Sunagawa, Kenji

doi:10.1152/ajpheart.00462.2014

Cited by 40 publications

(33 citation statements)

References 51 publications

(76 reference statements)

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“…The functional significance of the AngII effect on PVN astrocytes is further highlighted by our in vivo studies showing a contribution of PVN astrocytes to the AngII-evoked increase in sympathetic nerve activity and blood pressure. Our results are also consistent with a recent study showing that targeted-deletion of astrocyte AT1 receptors diminished sympathoexcitation in mice with heart failure 22 .…”

Section: Discussionsupporting

confidence: 93%

“…Yet, numerous studies, including our own, have shown AT1 receptor-mediated actions on astrocytes and microglial cells 20, 35 . Conversely, there is more consensus supporting increased AT1 receptor expression in glial cells in pathological conditions, including inflammation, hypertension and heart failure 22, 36 .…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, we showed that the magnitude of this tonic modality is dictated by the activity of astrocyte glutamate transporters (GLT1) that actively buffer extracellular glutamate 17 . Based on recent studies supporting the expression of AngII AT1 receptors in glial cells 20, 21 , and a contribution of astrocytes to AngII-driven sympathetic activity during heart failure 22 , we tested the hypothesis that astrocytes are key intermediaries for AngII actions in the PVN. Using a multidisciplinary approach combining patch-clamp recordings from presympathetic PVN neurons and astrocytes, along with whole-animal sympathetic nerve recordings and astrocyte-targeted gene manipulations, we show that AngII inhibits astrocyte GLT1 activity, enhancing extrasynaptic glutamate excitatory tone, thus indirectly stimulating neuronal activity and sympathoexcitatory outflow from the PVN, and that this effects involve astrocyte-derive oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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Astrocytes Contribute to Angiotensin II Stimulation of Hypothalamic Neuronal Activity and Sympathetic Outflow

et al. 2016

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Angiotensin II is a key neuropeptide that acting within the brain hypothalamic paraventricular nucleus regulates neurohumoral outflow to the circulation. Moreover, an exacerbated angiotensin II action within the paraventricular nucleus contributes to neurohumoral activation in hypertension. While angiotensin II effects involve changes in paraventricular nucleus neuronal activity, the precise underlying mechanisms, cellular targets, and distribution of angiotensin II receptors within the paraventricular nucleus remain largely unknown. Thus, whether angiotensin II effects involve direct actions on paraventricular neurons, or whether it acts via intermediary cells, such as astrocytes, is still controversial. To address this important gap in our knowledge, we used a multidisciplinary approach combining patch-clamp electrophysiology in presympathetic paraventricular neurons and astrocytes, along with in vivo sympathetic nerve recordings and astrocyte-targeted gene manipulations. We present evidence for a novel mechanism underlying central angiotensin II actions, which involves astrocytes as major intermediary cellular targets. We found that angiotensin II AT1 receptor mRNA is expressed in paraventricular astrocytes. Moreover, we report that AngII inhibited glutamate transporter function, increasing in turn extracellular glutamate levels. This resulted in the activation of neuronal extrasynaptic NMDA-receptors, increased presympathetic neuronal activity, enhanced sympathoexcitatory outflow, and increased blood pressure. Together, our studies support astrocytes as critical intermediary cell types underlying brain angiotensin II regulation of the circulation, and indicate that angiotensin II-mediated neuronal and sympathoexcitatory effects are dependent on a unique neuro-glial signaling modality involving non-synaptic glutamate transmission.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Astrocytes Contribute to Angiotensin II Stimulation of Hypothalamic Neuronal Activity and Sympathetic Outflow

et al. 2016

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“…Similarly, a link between AT 1 R and TLR4 in medicating microglial activation in the PVN has been reported (79). Interestingly, AT 1 R is upregulated in glial astrocytes after myocardial infarction, and glial-cell specific deletion of AT 1 R blunted sympathoexcitation in response to myocardial infarction (417). These studies implicate both neuroglial signaling and AT 1 R expression and action in cells other than neurons in the brain as mediating some of the pathological action of ANG II.…”

Section: Regulation Via Pvn At 1 Rmentioning

confidence: 84%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

773

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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“…Recently, we have demonstrated that targeted deletion of AT 1 R in astrocytes strikingly improved survival with prevention of left ventricular remodeling and sympathoinhibition in myocardial infarction-induced heart failure. 82) From these results, we believe that AT 1 R in astrocytes, not in neurons, have a key role in the pathophysiology of heart failure. Conclusion: Heart failure is a complex syndrome with sympathoexcitation, and no one doubts that excess sympathoexcitation should be the target of treatments for heart failure.…”

Section: Central Mechanisms Of Sympathoexcitation In Heart Failurementioning

confidence: 79%

Heart Failure as a Disruption of Dynamic Circulatory Homeostasis Mediated by the Brain

Kishi

2016

Int. Heart J.

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SummaryCirculatory homeostasis is associated with interactions between multiple organs, and the disruption of dynamic circulatory homeostasis could be considered as heart failure. The brain is the central unit integrating neural and neurohormonal information from peripheral organs and controlling peripheral organs using the autonomic nervous system. Heart failure is worsened by abnormal sympathoexcitation associated with baroreflex failure and/or chemoreflex activation, and by vagal withdrawal, and autonomic modulation therapies have benefits for heart failure. Recently, we showed that baroreflex failure induces striking volume intolerance independent of left ventricular dysfunction. Many studies have indicated that an overactive renin-angiotensin system, excess oxidative stress and excess inflammation, and/or decreased nitric oxide in the brain cause sympathoexcitation in heart failure. We have demonstrated that angiotensin II type 1 receptor (AT 1 R)-induced oxidative stress in the rostral ventrolateral medulla (RVLM), which is known as a vasomotor center, causes prominent sympathoexcitation in heart failure model rats. Interestingly, systemic infusion of angiotensin II directly affects brain AT 1 R with sympathoexcitation and left ventricular diastolic dysfunction. Moreover, we have demonstrated that targeted deletion of AT 1 R in astrocytes strikingly improved survival with prevention of left ventricular remodeling and sympathoinhibition in myocardial infarction-induced heart failure. From these results, we believe it is possible that AT 1 R in astrocytes, not in neurons, have a key role in the pathophysiology of heart failure. We would like to propose a novel concept that the brain works as a central processing unit integrating neural and hormonal input, and that the disruption of dynamic circulatory homeostasis mediated by the brain causes heart failure. (Int Heart J 2016; 57: 145-149)

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Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

Cited by 40 publications

References 51 publications

Astrocytes Contribute to Angiotensin II Stimulation of Hypothalamic Neuronal Activity and Sympathetic Outflow

Astrocytes Contribute to Angiotensin II Stimulation of Hypothalamic Neuronal Activity and Sympathetic Outflow

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Heart Failure as a Disruption of Dynamic Circulatory Homeostasis Mediated by the Brain

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