title: Adenosine 2A receptor modulates inflammation and phenotype in experimental abdominal aortic aneurysms.
abstract: Activation of the adenosine 2A receptor (A2AR) reduces inflammation in models of acute injury but contribution in development of chronic abdominal aortic aneurysms (AAAs) is unknown. Elastase perfusion to induce AAA formation in A2AR-knockout (A2ARKO) and C57BL6/J wild-type (WT) mice resulted in nearly 100% larger aneurysms in A2ARKO compared to WT at d 14 (P<0.05), with evidence of greater elastin fragmentation, more immune cell infiltration, and increased matrix metallatoproteinase (MMP) 9 expression (P<0.05). Separately, exogenous A2AR antagonism in elastase-perfused WT mice also resulted in larger aneurysms (P<0.05), while A2AR agonism limited aortic dilatation (P<0.05). Activated Thy-1.2(+) T lymphocytes from WT mice treated in vitro with A2AR antagonist increased cytokine production, and treatment with A2AR agonist decreased cytokine production (P<0.05 for all). Primary activated CD4(+) T lymphocytes from A2ARKO mice exhibited greater chemotaxis (P<0.05). A2AR antagonist increased chemotaxis of activated CD4(+) cells from WT mice in vitro, and A2AR agonist reduced this effect (P<0.05). A2AR activation attenuates AAA formation partly by inhibiting immune cell recruitment and reducing elastin fragmentation. These findings support augmenting A2AR signaling as a putative target for limiting aneurysm formation.
authors: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: Castigliano M
authors: CM
authors: Bhamidipati
authors: Gaurav S
authors: GS
authors: Mehta
authors: Christopher W
authors: CW
authors: Moehle
authors: Akshaya K
authors: AK
authors: Meher
authors: Gang
authors: G
authors: Su
authors: Navin G
authors: NG
authors: Vigneshwar
authors: Carlos
authors: C
authors: Barbery
authors: Ashish K
authors: AK
authors: Sharma
authors: Irving L
authors: IL
authors: Kron
authors: Victor E
authors: VE
authors: Laubach
authors: Gary K
authors: GK
authors: Owens
authors: Gilbert R
authors: GR
authors: Upchurch
authors: Gorav
authors: G
authors: Ailawadi
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010196:Pancreatic Elastase / Q000008:administration & dosage; D010627:Phenethylamines / Q000494:pharmacology; D010641:Phenotype; D043683:Receptors, Adenosine A2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D016207:Cytokines; D010627:Phenethylamines; D043683:Receptors, Adenosine A2; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000241:Adenosine
keywords: CD4+ T lymphocytes; GPCR signaling; immune modulation; inflammation; physiological regulation