Extracellular Acidification Activates cAMP Responsive Element Binding Protein via Na+/H+ Exchanger Isoform 1–Mediated Ca
            <sup>2+</sup>
            Oscillation in Central Nervous System Pericytes

Nakamura, Kuniyuki; Kamouchi, Masahiro; Arimura, Koichi; Nishimura, Ataru; Kuroda, Junya; Ishitsuka, Koji; Tokami, Himiko; Sugimori, Hiroshi; Ago, Tetsuro; Kitazono, Takanari

doi:10.1161/atvbaha.112.254946

Cited by 23 publications

(12 citation statements)

References 49 publications

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“…Under the culture conditions employed, spontaneous Ca 2+ oscillations were not observed, whereas a spontaneous transient rise in Ca 2+ was only occasionally encountered. Finally, considering that extracellular acidosis induces Ca 2+ oscillations [22] , we confirmed that pH of the culture medium was not changed after the addition of butyrate (medium pH = 7.21, medium + sodium butyrate pH = 7.26, conditions: 37°C and 5% CO 2 ).…”

Section: Resultssupporting

confidence: 70%

Butyrate Increases Intracellular Calcium Levels and Enhances Growth Hormone Release from Rat Anterior Pituitary Cells via the G-Protein-Coupled Receptors GPR41 and 43

et al. 2014

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Butyrate is a short-chain fatty acid (SCFA) closely related to the ketone body ß-hydroxybutyrate (BHB), which is considered to be the major energy substrate during prolonged exercise or starvation. During fasting, serum growth hormone (GH) rises concomitantly with the accumulation of BHB and butyrate. Interactions between GH, ketone bodies and SCFA during the metabolic adaptation to fasting have been poorly investigated to date. In this study, we examined the effect of butyrate, an endogenous agonist for the two G-protein-coupled receptors (GPCR), GPR41 and 43, on non-stimulated and GH-releasing hormone (GHRH)-stimulated hGH secretion. Furthermore, we investigated the potential role of GPR41 and 43 on the generation of butyrate-induced intracellular Ca2+ signal and its ultimate impact on hGH secretion. To study this, wt-hGH was transfected into a rat pituitary tumour cell line stably expressing the human GHRH receptor. Treatment with butyrate promoted hGH synthesis and improved basal and GHRH-induced hGH-secretion. By acting through GPR41 and 43, butyrate enhanced intracellular free cytosolic Ca2+. Gene-specific silencing of these receptors led to a partial inhibition of the butyrate-induced intracellular Ca2+ rise resulting in a decrease of hGH secretion. This study suggests that butyrate is a metabolic intermediary, which contributes to the secretion and, therefore, to the metabolic actions of GH during fasting.

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Section: Resultssupporting

confidence: 70%

Butyrate Increases Intracellular Calcium Levels and Enhances Growth Hormone Release from Rat Anterior Pituitary Cells via the G-Protein-Coupled Receptors GPR41 and 43

et al. 2014

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“…In addition to AMPK, activated CaMKKβ phosphorylates and activates CaMK1 (Thr177) (Figure 4D). This is a key observation as in addition to PKA, CREB (ser133) can be phosphorylated by CaMK1 [37], [38], as seen in Figure 4D and E. Although such serine phosphorylation of CREB could also result from the small observed increase in cAMP, inhibition of CaMKKβ, and thereby CaMK1, with the CaMKKβ inhibitor STO-609 (further discussed below) also inhibited phosphorylation of CREB (Figure S2), indicating that it is dependent on CaMKKβ activity.…”

Section: Resultsmentioning

confidence: 74%

Glucagon-Like Peptide-1 (GLP-1) Analog Liraglutide Inhibits Endothelial Cell Inflammation through a Calcium and AMPK Dependent Mechanism

et al. 2014

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Liraglutide is a glucagon-like peptide-1 (GLP-1) mimetic used for the treatment of Type 2 diabetes. Similar to the actions of endogenous GLP-1, liraglutide potentiates the post-prandial release of insulin, inhibits glucagon release and increases satiety. Recent epidemiological studies and clinical trials have suggested that treatment with GLP-1 mimetics may also diminish the risk of cardiovascular disease in diabetic patients. The mechanism responsible for this effect has yet to be determined; however, one possibility is that they might do so by a direct effect on vascular endothelium. Since low grade inflammation of the endothelium is an early event in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), we determined the effects of liraglutide on inflammation in cultured human aortic endothelial cells (HAECs). Liraglutide reduced the inflammatory responses to TNFα and LPS stimulation, as evidenced by both reduced protein expression of the adhesion molecules VCAM-1 and E-Selectin, and THP-1 monocyte adhesion. This was found to result from increased cell Ca2+ and several molecules sensitive to Ca2+ with known anti inflammatory actions in endothelial cells, including CaMKKβ, CaMKI, AMPK, eNOS and CREB. Treatment of the cells with STO-609, a CaMKK inhibitor, diminished both the activation of AMPK, CaMKI and the inhibition of TNFα and LPS-induced monocyte adhesion by liraglutide. Likewise, expression of an shRNA against AMPK nullified the anti-inflammatory effects of liraglutide. The results indicate that liraglutide exerts a strong anti-inflammatory effect on HAECs. They also demonstrate that this is due to its ability to increase intracellular Ca2+ and activate CAMKKβ, which in turn activates AMPK.

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“…4). Among possible factors produced by PDGFRb -positive cells, we focused on IL6 because it can be produced from mesenchymal cells, including pericytes (Gaceb et al, 2018), and can induce the phosphorylation of STAT3 and AKT, both potent intracellular transducers of activation and survival/proliferation of astrocytes (Yamashita et al, 2005;Nakamura et al, 2012;Wanner et al, 2013;Gu et al, 2016). It is also reported that IL6 can induce poststroke angiogenesis and repair (Gertz et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Pericyte-Mediated Tissue Repair through PDGFRβ Promotes Peri-Infarct Astrogliosis, Oligodendrogenesis, and Functional Recovery after Acute Ischemic Stroke

Shibahara

Ago

Nakamura

et al. 2020

eNeuro

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Visual Abstract Significance StatementPericyte-mediated fibrotic tissue repair is a major histological change within the infarct area during the subacute phase after ischemic stroke. Whether fibrotic repair is beneficial or detrimental to post-stroke functional recovery is highly debated. Here, we demonstrate that inhibition of fibrotic repair in mice by heterozygous deletion of platelet-derived growth factor receptor b (PDGFRb ) (Pdgfrb 1/-) significantly attenuates functional recovery after ischemic stroke. Pericyte-derived PDGFRb -positive cells within the infarct area produced trophic factors that activated astrocytes, thereby enhancing peri-infarct astrogliosis. Furthermore, astrocytes, conditioned with PDGF-BB-stimulated pericyte culture medium, promoted oligodendrocyte (OL) differentiation and a myelinating response. Peri-infarct oligodendrogenesis and re-myelination within areas of astrogliosis was significantly attenuated in Pdgfrb 1/mice. Pericyte-mediated tissue repair is beneficial for post-stroke functional recovery and is a potential therapeutic target.March/April 2020, 7(2) ENEURO.0474-19.2020 1-20Research Article: Theory/New Concepts tioned medium (PCM), particularly when treated with platelet-derived growth factor subunit B (PDGFB) homodimer (PDGF-BB; PCM/PDGF-BB), activated STAT3 and enhanced the proliferation and activity of cultured astrocytes. Although peri-infarct proliferation of oligodendrocyte (OL) precursor cells (OPCs) was induced promptly after pMCAO regardless of intrainfarct repair, OPC differentiation and remyelination were significantly attenuated in Pdgfrb 1/mice. Consistently, astrocyte-CM (ACM) promoted OPC differentiation and myelination, which were enhanced remarkably by adding PCM/PDGF-BB to the medium. Post-stroke functional recovery correlated well with the extent and process of intrainfarct repair and peri-infarct oligodendrogenesis. Overall, pericyte-mediated intrainfarct fibrotic repair through PDGFRb may promote functional recovery through enhancement of peri-infarct oligodendrogenesis as well as astrogliosis after acute ischemic stroke.

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Extracellular Acidification Activates cAMP Responsive Element Binding Protein via Na+/H+ Exchanger Isoform 1–Mediated Ca ²⁺ Oscillation in Central Nervous System Pericytes

Abstract: The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl

Cited by 23 publications

References 49 publications

Butyrate Increases Intracellular Calcium Levels and Enhances Growth Hormone Release from Rat Anterior Pituitary Cells via the G-Protein-Coupled Receptors GPR41 and 43

Butyrate Increases Intracellular Calcium Levels and Enhances Growth Hormone Release from Rat Anterior Pituitary Cells via the G-Protein-Coupled Receptors GPR41 and 43

Glucagon-Like Peptide-1 (GLP-1) Analog Liraglutide Inhibits Endothelial Cell Inflammation through a Calcium and AMPK Dependent Mechanism

Pericyte-Mediated Tissue Repair through PDGFRβ Promotes Peri-Infarct Astrogliosis, Oligodendrogenesis, and Functional Recovery after Acute Ischemic Stroke

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Extracellular Acidification Activates cAMP Responsive Element Binding Protein via Na+/H+ Exchanger Isoform 1–Mediated Ca 2+ Oscillation in Central Nervous System Pericytes

Abstract: The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl

Cited by 23 publications

References 49 publications

Butyrate Increases Intracellular Calcium Levels and Enhances Growth Hormone Release from Rat Anterior Pituitary Cells via the G-Protein-Coupled Receptors GPR41 and 43

Butyrate Increases Intracellular Calcium Levels and Enhances Growth Hormone Release from Rat Anterior Pituitary Cells via the G-Protein-Coupled Receptors GPR41 and 43

Glucagon-Like Peptide-1 (GLP-1) Analog Liraglutide Inhibits Endothelial Cell Inflammation through a Calcium and AMPK Dependent Mechanism

Pericyte-Mediated Tissue Repair through PDGFRβ Promotes Peri-Infarct Astrogliosis, Oligodendrogenesis, and Functional Recovery after Acute Ischemic Stroke

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Extracellular Acidification Activates cAMP Responsive Element Binding Protein via Na+/H+ Exchanger Isoform 1–Mediated Ca ²⁺ Oscillation in Central Nervous System Pericytes