Adenosine Receptors As Drug Targets for Treatment of Pulmonary Arterial Hypertension

Alencar, Alexandre; Montes, Guilherme Carneiro; Barreiro, Eliezer J.; Sudo, Roberto T.; Zapata‐Sudo, Gisele

doi:10.3389/fphar.2017.00858

Cited by 27 publications

(28 citation statements)

References 222 publications

(299 reference statements)

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“…P2YRs belong to the δ-branch of class A G-protein-coupled receptor (GPCR) family and contain seven hydrophobic transmembrane regions connected by three extracellular loops and three intracellular loops ( 3 ). Based on the phylogenetic and structural divergence, two distinct P2YR subgroups have been identified ( 23 ). The first group contains P2Y 1/2/4/6/11 Rs, with a sequence homology of 35–52% in amino-acid composition and the presence of a Y–Q/K–X–X–R defining motif in the transmembrane α-helix 7.…”

Section: Purinergic Receptorsmentioning

confidence: 99%

“…The second group contains P2Y 12/13/14 Rs, with a sequence homology of 47–48% and the presence of the K–E–X–X–L motif in transmembrane α-helix 7. Moreover, the two subgroups also differ in their primary coupling to G-proteins ( 23 ). P2Y 1/2/4/6/11 Rs primarily couple to G q /G 11 and initiate phospholipase C/inositol trisphosphate/diacylglycerol pathway to increase intracellular calcium, whereas P2Y 12/13/14 Rs principally couple to G i/0 and inhibit adenylate cyclase (AC) to decrease intracellular cyclic AMP (cAMP).…”

Section: Purinergic Receptorsmentioning

confidence: 99%

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Purinergic Regulation of Neutrophil Function

Wang

Chen

2018

Front. Immunol.

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Purinergic signaling, which utilizes nucleotides (particularly ATP) and adenosine as transmitter molecules, plays an essential role in immune system. In the extracellular compartment, ATP predominantly functions as a pro-inflammatory molecule through activation of P2 receptors, whereas adenosine mostly functions as an anti-inflammatory molecule through activation of P1 receptors. Neutrophils are the most abundant immune cells in circulation and have emerged as an important component in orchestrating a complex series of events during inflammation. However, because of the destructive nature of neutrophil-derived inflammatory agents, neutrophil activation is fine-tuned, and purinergic signaling is intimately involved in this process. Indeed, shifting the balance between P2 and P1 signaling is critical for neutrophils to appropriately exert their immunologic activity. Here, we review the role of purinergic signaling in regulating neutrophil function, and discuss the potential of targeting purinergic signaling for the treatment of neutrophil-associated infectious and inflammatory diseases.

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Section: Purinergic Receptorsmentioning

confidence: 99%

Section: Purinergic Receptorsmentioning

confidence: 99%

Purinergic Regulation of Neutrophil Function

Wang

Chen

2018

Front. Immunol.

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“…PHT is the most serious complication of ASD and the most significant cause of early mortality and reduced functional capacity in these patients (10,11). Previous studies showed that patients with PHT had endothelial dysfunction independent of its cause (12,13). In view of this, we considered that PHT would develop, and thus PWV might be elevated in patients with ASD.…”

Section: Discussionmentioning

confidence: 99%

Pre and Post Operative Evaluation of The Effect of Atrial Septal Defect on Systemic Circulation Via Pulse Wave Velocity

Keleşoğlu¹,

Elçik²,

Tunçay³

et al. 2019

Erciyes Med J

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The aim of the present study was to examine whether endothelial function is affected in patients with atrial septal defect (ASD) of secundum type and to determine the changes that might occur in endothelial function after the defect was closed by the transcatheter method by using the pulse wave velocity (PWV) technique. Materials and Methods: A total of 54 patients with ASD type and 40 healthy individuals were included in the study. All patients underwent transthoracic echocardiography and PWV measurements to evaluate the endothelial function prior to and 1 month after the closure procedure. Results: PWV values were significantly higher in patients with ASD than in healthy subjects (7.5±1.2 m/s vs. 6.1±1.0 m/s, p<0.001). Systolic pulmonary arterial pressure (PAP), right ventricular diameter, and PWV values were significantly lower at 1 month of follow-up after the procedure than at baseline (p<0.001). However left ventricular ejection fraction, left ventricular end-diastolic diameter (LVEDD), and tricuspid annular plane systolic excursion values increased significantly after the procedure component (p<0.001, p=0.002, and p<0.001, respectively). Conclusion: It was observed that following closure of the ASD by the transcatheter route, the PWV values were significantly reduced in the right cardiac chambers, and the systolic PAP was improved. This result has shown us that ASD closure may benefit from endothelial dysfunction.

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“…Taken together, these results demonstrated the therapeutic potential of abrogation of ADORA2B signaling in lung injury and PH; however, it was not known whether vascular ADORA2B could contribute directly to the development of PH in an in vivo setting. Similarly, the role of ADORA2B in clinical or experimental models of PAH had not been addressed until now (Alencar et al, 2017 ). Strikingly, our results show that switching-off vascular smooth muscle ADORA2B is able to prevent HX-SU and BLM induced PH without altering fibrotic deposition levels in BLM-exposed mice.…”

Section: Discussionmentioning

confidence: 99%

Switching-Off Adora2b in Vascular Smooth Muscle Cells Halts the Development of Pulmonary Hypertension

Mertens

Hanmandlu

et al. 2018

Front. Physiol.

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Background: Pulmonary hypertension (PH) is a devastating and progressive disease characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and remodeling of the lung vasculature. Adenosine signaling through the ADORA2B receptor has previously been implicated in disease progression and tissue remodeling in chronic lung disease. In experimental models of PH associated with chronic lung injury, pharmacological or genetic inhibition of ADORA2B improved markers of chronic lung injury and hallmarks of PH. However, the contribution of ADORA2B expression in the PASMC was not fully evaluated.Hypothesis: We hypothesized that adenosine signaling through the ADORA2B receptor in PASMC mediates the development of PH.Methods: PASMCs from controls and patients with idiopathic pulmonary arterial hypertension (iPAH) were characterized for expression levels of all adenosine receptors. Next, we evaluated the development of PH in ADORA2Bf/f-Transgelin (Tagln)cre mice. These mice or adequate controls were exposed to a combination of SUGEN (SU5416, 20 mg/kg/b.w. IP) and hypoxia (10% O2) for 28 days (HX-SU) or to chronic low doses of bleomycin (BLM, 0.035U/kg/b.w. IP). Cardiovascular readouts including right ventricle systolic pressures (RVSPs), Fulton indices and vascular remodeling were determined. Using PASMCs we identified ADORA2B-dependent mediators involved in vascular remodeling. These mediators: IL-6, hyaluronan synthase 2 (HAS2) and tissue transglutaminase (Tgm2) were determined by RT-PCR and validated in our HX-SU and BLM models.Results: Increased levels of ADORA2B were observed in PASMC from iPAH patients. ADORA2Bf/f-Taglncre mice were protected from the development of PH following HX-SU or BLM exposure. In the BLM model of PH, ADORA2Bf/f- Taglncre mice were not protected from the development of fibrosis. Increased expression of IL-6, HAS2 and Tgm2 was observed in PASMC in an ADORA2B-dependent manner. These mediators were also reduced in ADORA2Bf/f- Taglncre mice exposed to HX-SU or BLM.Conclusions: Our studies revealed ADORA2B-dependent increased levels of IL-6, hyaluronan and Tgm2 in PASMC, consistent with reduced levels in ADORA2Bf/f- Taglncre mice exposed to HX-SU or BLM. Taken together, our data indicates that ADORA2B on PASMC mediates the development of PH through the induction of IL-6, hyaluronan and Tgm2. These studies point at ADORA2B as a therapeutic target to treat PH.

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Adenosine Receptors As Drug Targets for Treatment of Pulmonary Arterial Hypertension

Cited by 27 publications

References 222 publications

Purinergic Regulation of Neutrophil Function

Purinergic Regulation of Neutrophil Function

Pre and Post Operative Evaluation of The Effect of Atrial Septal Defect on Systemic Circulation Via Pulse Wave Velocity

Switching-Off Adora2b in Vascular Smooth Muscle Cells Halts the Development of Pulmonary Hypertension

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