scholarly journals Adenosine A2a Receptors Improve Hypoxic Pulmonary Arterial Hypertension Via Mitochondrial ATP-sensitive Potassium Channels

2021 ◽  
Author(s):  
Lihuang Su ◽  
Gexiang Cai ◽  
Lin Zhang ◽  
Zhimin Cui ◽  
Lin Yang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Remodeling ◽  
Caspase 9 ◽  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
Remodeling Index ◽  
Pulmonary Arterial ◽  
Adenosine A2a

IntroductionThis study is aimed to explore the effects of Adenosine A2a receptors (A2aR) on hypoxia-induced pulmonary hypertension (HPH) via mitochondrial ATP-sensitive potassium channels (MitoKATP) in vivo and in vitro.Material and methodsUsing wild-type (WT) and A2aR-deficient (A2aR-/-) mice; hypoxic pulmonary artery smooth muscle cells (PASMCs) were induced by a 24-hours hypoxia exposure. Mice and PASMCs were treated with the A2aR agonist CGS21680, MitoKATP blocker 5-hydroxydecanoic acid sodium salt (5HD), or MitoKATP agonist diazoxide. Mitochondrial morphology was observed by electron microscopy. The mitochondrial membrane potential (Δψm); invasive hemodynamic parameters; right ventricular (RV) hypertrophy index; pulmonary arterial remodeling index; proliferative and apoptotic indexes; protein expression levels of A2aR, Bax, Bcl-2, and Caspase-9; and release of cytochrome C from the mitochondria to the cytoplasm were measured.ResultsIn vitro, hypoxia induced the opening of MitoKATP. The up-regulation of A2aR reduced the opening of MitoKATP, and the blocking of MitoKATP or activating A2aR promoted mitochondria-dependent apoptosis of PASMCs. In vivo, compared with WT mice, A2aR-/- mice displayed increased RV systolic pressure, RV hypertrophy index, and pulmonary arterial remodeling index. The expression levels of Bax, cytochrome C, and Caspase-9 were higher and Bcl-2 expression was lower in A2aR-/- mice than in WT mice. CGS21680 could reverse hypoxia-induced hemodynamic changes, RV hypertrophy, and pulmonary arterial remodeling as well as abnormal proliferation and apoptosis resistance in WT mice with pulmonary hypertension (PH).ConclusionsA2aR induced the mitochondrial-dependent apoptosis pathway and inhibited PASMC proliferation by blocking MitoKATP, thereby inhibiting pulmonary vascular structural remodeling and reducing PH.

scholarly journals Mutual promotion of FGF21 and PPARγ attenuates hypoxia-induced pulmonary hypertension

2019 ◽  
Vol 244 (3) ◽  
pp. 252-261 ◽  
Author(s):  
Gexiang Cai ◽  
Jingjing Liu ◽  
Meibin Wang ◽  
Lihuang Su ◽  
Mengsi Cai ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mouse Lung ◽  
Fibroblast Growth Factor 21 ◽  
Arterial Remodeling ◽  
Collagen Deposition ◽  
Pparγ Agonist ◽  
Pulmonary Arterial ◽  
The Relationship

Fibroblast growth factor 21 (FGF21), a primarily liver-derived endocrine factor, has the beneficial effect of protecting blood vessels. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear transcription factor, has been reported to effectively inhibit pulmonary hypertension (PH). The purpose of this study is to investigate the role of FGF21 in hypoxia-induced PH (HPH) and explore the relationship between FGF21 and PPARγ in this disorder. Adult C57BL/6 mice were subjected to four weeks of hypoxia to establish a PH model. The effects of FGF21 and PPARγ agonists and antagonists were investigated in HPH mice, as well as the relationship between FGF21 and PPARγ in this model. Moreover, we investigated the underlying mechanisms of this relationship between FGF21 and PPARγ in vivo and in vitro. In vivo, we found that hypoxia resulted in pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial remodeling, and pulmonary arterial collagen deposition. Furthermore, hypoxia decreased FGF21 and PPARγ levels. These changes were reversed by exogenous FGF21 and a PPARγ agonist and were further enhanced by a PPARγ antagonist. The hypoxia-induced decrease in β-klotho (KLB) expression was improved by the PPARγ agonist and further reduced by the PPARγ antagonist. Exogenous FGF21 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) and PPARγ coactivator-1α (PGC-1α) expression in PH mouse lung homogenates. In vitro, we found that knockdown of AMPK or using an AMPK antagonist inhibited the FGF21-mediated up-regulation of PPARγ expression, and the PPARγ-mediated up-regulation of FGF21 expression was inhibited by knockdown of KLB. These results indicated that FGF21 exerts protective effects in inhibiting HPH. FGF21 and PPARγ mutually promote each other’s expression in HPH via the AMPK/PGC-1α pathway and KLB protein. Impact statement In this study, we reported for the first time that FGF21 alleviated hypoxia-induced pulmonary hypertension through attenuation of increased pulmonary arterial pressure, pulmonary arterial remodeling and collagen deposition in vivo, and we confirmed the mutual promotion of FGF21 and PPARγ in hypoxia-induced pulmonary hypertension. Additionally, we found that FGF21 and PPARγ mutually promote each other’s expression via the AMPK/PGC-1α pathway and KLB protein in vitro and in vivo. Pulmonary hypertension is a progressive and serious pathological phenomenon with a poor prognosis, and current therapies are highly limited. Our results provide novel insight into potential clinical therapies for pulmonary hypertension and establish the possibility of using this drug combination and potential dosage reductions in clinical settings.

scholarly journals Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency–induced autoimmunity via adenosine A2A receptors

2016 ◽  
Vol 214 (1) ◽  
pp. 107-123 ◽  
Author(s):  
Baokun He ◽  
Thomas K. Hoang ◽  
Ting Wang ◽  
Michael Ferris ◽  
Christopher M. Taylor ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Lactobacillus Reuteri ◽  
Major Effect ◽  
Th2 Cells ◽  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
Adenosine A2a ◽  
Th1 And Th2

Regulatory T (T reg) cell deficiency causes lethal, CD4+ T cell–driven autoimmune diseases. Stem cell transplantation is used to treat these diseases, but this procedure is limited by the availability of a suitable donor. The intestinal microbiota drives host immune homeostasis by regulating the differentiation and expansion of T reg, Th1, and Th2 cells. It is currently unclear if T reg cell deficiency–mediated autoimmune disorders can be treated by targeting the enteric microbiota. Here, we demonstrate that Foxp3+ T reg cell deficiency results in gut microbial dysbiosis and autoimmunity over the lifespan of scurfy (SF) mouse. Remodeling microbiota with Lactobacillus reuteri prolonged survival and reduced multiorgan inflammation in SF mice. L. reuteri changed the metabolomic profile disrupted by T reg cell deficiency, and a major effect was to restore levels of the purine metabolite inosine. Feeding inosine itself prolonged life and inhibited multiorgan inflammation by reducing Th1/Th2 cells and their associated cytokines. Mechanistically, the inhibition of inosine on the differentiation of Th1 and Th2 cells in vitro depended on adenosine A2A receptors, which were also required for the efficacy of inosine and of L. reuteri in vivo. These results reveal that the microbiota–inosine–A2A receptor axis might represent a potential avenue for combatting autoimmune diseases mediated by T reg cell dysfunction.

Afferent arteriolar adenosine A2a receptors are coupled to KATP in in vitro perfused hydronephrotic rat kidney

1999 ◽  
Vol 277 (6) ◽  
pp. F926-F933 ◽  
Author(s):  
Lilong Tang ◽  
Michael Parker ◽  
Qing Fei ◽  
Rodger Loutzenhiser
Keyword(s):  
Rat Kidney ◽  
Afferent Arteriole ◽  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
High Affinity ◽  
Vasodilatory Response ◽  
Renal Microvasculature ◽  
Adenosine A2a ◽  
Arteriolar Vasodilation

Adenosine is known to exert dual actions on the afferent arteriole, eliciting vasoconstriction, by activating A1 receptors, and vasodilation at higher concentrations, by activating lower-affinity A2 receptors. We could demonstrate both of these known adenosine responses in the in vitro perfused hydronephrotic rat kidney. Thus, 1.0 μM adenosine elicited a transient vasoconstriction blocked by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and 10–30 μM adenosine reversed KCl-induced vasoconstriction. However, when we examined the effects of adenosine on pressure-induced afferent arteriolar vasoconstriction, we observed a third action. In this setting, a high-affinity adenosine vasodilatory response was observed at concentrations of 10–300 nM. This response was blocked by both 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM-241385) and glibenclamide and was mimicked by 2-phenylaminoadenosine (CV-1808) (IC50 of 100 nM), implicating adenosine A2a receptors coupled to ATP-sensitive K channels (KATP). Like adenosine, 5′- N-ethylcarboxamidoadenosine (NECA) elicited both glibenclamide-sensitive and glibenclamide-insensitive vasodilatory responses. The order of potency for the glibenclamide-sensitive component was NECA > adenosine = CV-1808. Our findings suggest that, in addition to the previously described adenosine A1 and low-affinity A2b receptors, the renal microvasculature is also capable of expressing high-affinity adenosine A2areceptors. This renal adenosine receptor elicits afferent arteriolar vasodilation at submicromolar adenosine levels by activating KATP.

In vivo biodistribution of [N-11C-methyl]KF 17837 using 3-D-PET: Evaluation as a ligand for the study of adenosine A2A receptors

1997 ◽  
Vol 24 (2) ◽  
pp. 187-191 ◽  
Author(s):  
Sharon Stone-Elander ◽  
Jan-Olov Thorell ◽  
Lars Eriksson ◽  
Bertil B. Fredholm ◽  
Martin Ingvar
Keyword(s):  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
In Vivo Biodistribution ◽  
Adenosine A2a

scholarly journals Regulation of the phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine D1, dopamine D2, and adenosine A2A receptors

2000 ◽  
Vol 97 (4) ◽  
pp. 1856-1860 ◽  
Author(s):  
P. Svenningsson ◽  
M. Lindskog ◽  
C. Ledent ◽  
M. Parmentier ◽  
P. Greengard ◽  
...  
Keyword(s):  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
Dopamine D2 ◽  
Adenosine A2a

scholarly journals Eosinophils are necessary for pulmonary arterial remodeling in a mouse model of eosinophilic inflammation-induced pulmonary hypertension

2011 ◽  
Vol 301 (6) ◽  
pp. L927-L936 ◽  
Author(s):  
M. Weng ◽  
D. M. Baron ◽  
K. D. Bloch ◽  
A. D. Luster ◽  
J. J. Lee ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mouse Model ◽  
Vascular Inflammation ◽  
Arterial Remodeling ◽  
Eosinophilic Inflammation ◽  
Eosinophil Recruitment ◽  
Interleukin 5 ◽  
Pulmonary Arterial ◽  
Deficient Mice

There is increasing evidence that inflammation plays a pivotal role in the pathogenesis of some forms of pulmonary hypertension (PH). We recently demonstrated that deficiency of adiponectin (APN) in a mouse model of PH induced by eosinophilic inflammation increases pulmonary arterial remodeling, pulmonary pressures, and the accumulation of eosinophils in the lung. Based on these data, we hypothesized that APN deficiency exacerbates PH indirectly by increasing eosinophil recruitment. Herein, we examined the role of eosinophils in the development of inflammation-induced PH. Elimination of eosinophils in APN-deficient mice by treatment with anti-interleukin-5 antibody attenuated pulmonary arterial muscularization and PH. In addition, we observed that transgenic mice that are devoid of eosinophils also do not develop pulmonary arterial muscularization in eosinophilic inflammation-induced PH. To investigate the mechanism by which APN deficiency increased eosinophil accumulation in response to an allergic inflammatory stimulus, we measured expression levels of the eosinophil-specific chemokines in alveolar macrophages isolated from the lungs of mice with eosinophilic inflammation-induced PH. In these experiments, the levels of CCL11 and CCL24 were higher in macrophages isolated from APN-deficient mice than in macrophages from wild-type mice. Finally, we demonstrate that the extracts of eosinophil granules promoted the proliferation of pulmonary arterial smooth muscle cells in vitro. These data suggest that APN deficiency may exacerbate PH, in part, by increasing eosinophil recruitment into the lung and that eosinophils could play an important role in the pathogenesis of inflammation-induced PH. These results may have implications for the pathogenesis and treatment of PH caused by vascular inflammation.

Characterisation of anti-inflammatory effects of STW5 and STW6 on rat small intestine in vitro: Involvement of adenosine A2A receptors

Planta Medica ◽  
2007 ◽  
Vol 73 (09) ◽  
Author(s):  
K Nieber ◽  
S Michael ◽  
CE Müller ◽  
O Kelber
Keyword(s):  
Small Intestine ◽  
Rat Small Intestine ◽  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
Anti Inflammatory ◽  
Adenosine A2a

Caffeine and adenosine A2A receptors rescue neuronal development in vitro of frontal cortical neurons in a rat model of attention deficit and hyperactivity disorder

2020 ◽  
Vol 166 ◽  
pp. 107782 ◽  
Author(s):  
Catiane B. Alves ◽  
Amanda S. Almeida ◽  
Daniela M. Marques ◽  
Ana Helena L. Faé ◽  
Ana Carolina L. Machado ◽  
...  
Keyword(s):  
Rat Model ◽  
Attention Deficit ◽  
Cortical Neurons ◽  
Neuronal Development ◽  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
Hyperactivity Disorder ◽  
Development In Vitro ◽  
Adenosine A2a

Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors

2007 ◽  
Vol 26 (4) ◽  
pp. 843-851 ◽  
Author(s):  
Onintza Sagredo ◽  
José A. Ramos ◽  
Alessandra Decio ◽  
Raphael Mechoulam ◽  
Javier Fernández-Ruiz
Keyword(s):  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
Nitropropionic Acid ◽  
Adenosine A2a ◽  
3 Nitropropionic Acid
Sign in / Sign up

Export Citation Format

Share Document