Microglia activation in the hypothalamic PVN following myocardial infarction

Rana, Indrajeetsinh; Stebbing, Margaret Susanne; Kompa, A.; Kelly, Darren J.; Krum, Henry; Badoer, Emilio

doi:10.1016/j.brainres.2010.02.028

Cited by 77 publications

(75 citation statements)

References 59 publications

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“…Within the PVN, ANG II has been associated with increased microglial activation and increased expression of proinflammatory cytokines and the transcription factor NF-B during these pathological conditions (11,61,71,87). In addition, we recently showed that ANG II contributes to blood-brain barrier disruption within the PVN during hypertension, promoting leakage of circulating ANG II, which targets microglia within this nucleus (5).…”

Section: Functional Implicationsmentioning

confidence: 98%

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Biancardi

Stranahan

Krause

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

106

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II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT 1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (ϳ65% increase, P Ͻ 0.001), an effect that was blunted in the absence of functional TLR4. ANG II increased ROS production, as indicated by dihydroethidium fluorescence, within the PVN of rats and mice (P Ͻ 0.0001 in both cases), effects that were also dependent on the presence of functional TLR4. The microglial inhibitor minocycline attenuated ANG II-mediated ROS production, yet ANG II effects persisted in PVN single-minded 1-AT 1a knockout mice, supporting the contribution of a non-neuronal source (likely microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT 1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN. ANGIOTENSIN II (ANG II) plays a critical role in fluid balance and hemodynamic regulation (25). Within the central nervous system (CNS), ANG II acting through ANG II type 1 a (AT 1a ) receptors (AT 1a R) has been shown to be implicated in the regulation of sympathetic and neuroendocrine outputs from the brain (45, 49, 50). The paraventricular nucleus (PVN) of the hypothalamus has been recognized as a critical neuronal substrate mediating central ANG II actions, thus playing a critical role in ANG II-mediated neurohumoral responses (23, 78). Indeed, a large body of evidence supports enhanced angiotensinergic actions within the CNS, including the PVN, as a key pathophysiological mechanism involved in cardiovascular diseases, including hypertension and heart failure (37,60,78,80,88). However, despite its importance, the precise mechanisms and cellular/ molecular targets underlying ANG II signaling within the CNS are incompletely understood.Inflammation and oxidative stress have emerged as novel mechanisms by which central ANG II mediates its deleterious effects. For example, studies have shown that pressor and sympathetic responses to central ANG II are mediated by superoxide within the PVN (8, 22). Likewise, several studie...

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Section: Functional Implicationsmentioning

confidence: 98%

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Biancardi

Stranahan

Krause

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

106

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“…Therefore, we consider that GFAP-specific AT 1 R knockout could inhibit sympathetic activity by reducing oxidative stress in astrocytes. In addition, microglia in the paraventricular nucleus of the hypothalamus are activated after MI and contribute to LV remodeling (38). Astrocytes and microglia interact to regulate each other's function and neuronal function, and astrocytes also produce anti-inflammatory cytokines and neurotrophic factors that promote central nervous system repair (8).…”

Section: Discussionmentioning

confidence: 99%

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

Isegawa

Hirooka

Katsuki

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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“…Standard immunohistochemical procedures were performed as previously described [21,22]. Briefly, rats were anesthetized with chloral hydrate and perfused transcardially with ice-cold 0.9% saline followed by 4% PFA.…”

Section: Methodsmentioning

confidence: 99%

Neurogenin 2 Converts Mesenchymal Stem Cells into a Neural Precursor Fate and Improves Functional Recovery after Experimental Stroke

Cheng

Hao

et al. 2014

Cell Physiol Biochem

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Background: Neurogenin2 (Ngn2) is a proneural gene that directs neuronal differentiation of progenitor cells during development. Here, we investigated whether Ngn2 can reprogram MSCs to adopt a neural precursor fate and enhance the therapeutic effects of MSCs after experimental stroke. Methods: In vitro, MSCs were transfected with lenti-GFP or lenti-Ngn2. Following neuronal induction, cells were identified by immunocytochemistry, Western blot and electrophysiological analyses. In a stroke model induced by transient right middle cerebral artery occlusion (MCAO), PBS, GFP-MSCs or Ngn2-MSCs were injected 1 day after MCAO. Behavioral tests, neurological and immunohistochemical assessments were performed. Results: In vitro, Ngn2-MSCs expressed neural stem cells markers (Pax6 and nestin) and lost the potential to differentiate into mesodermal cell types. Following neural induction, Ngn2-MSCs expressed higher levels of neuron-specific proteins MAP2, Tuj1 and NeuN, and also expressed voltage-gated Na+ channel, which was absent in GFP-MSCs. In vivo, after transplantation, Ngn2-MSCs significantly reduced apoptotic cells, decreased infarct volume, and increased the expression of VEGF and BDNF. Finally, Ngn2-MSCs treated animals showed the highest functional recovery among the three groups. Conclusions: Ngn2 was sufficient to convert MSCs into a neural precursor fate and transplantation of Ngn2-MSCs was advantageous for the treatment of stroke rats.

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Microglia activation in the hypothalamic PVN following myocardial infarction

Cited by 77 publications

References 59 publications

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

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

Neurogenin 2 Converts Mesenchymal Stem Cells into a Neural Precursor Fate and Improves Functional Recovery after Experimental Stroke

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Microglia activation in the hypothalamic PVN following myocardial infarction

Cited by 77 publications

References 59 publications

Cross talk between AT1receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Cross talk between AT1receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

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

Neurogenin 2 Converts Mesenchymal Stem Cells into a Neural Precursor Fate and Improves Functional Recovery after Experimental Stroke

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Product

Resources

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Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

Cross talk between AT₁receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus