title: Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis.
abstract: Atherosclerosis is a chronic inflammatory disease of the vessel wall. Recent evidence suggests that chronic vascular inflammation ensues as an imbalance between pro- and anti-inflammatory mediators. Recently identified lipid mediators (eg, lipoxins and resolvins) play active roles in promoting the resolution of inflammation. Alterations in vascular smooth muscle cell (VSMC) phenotype, which manifest as a loss of contractile protein expression and increased proliferation and migration, are prominent mechanistic features of both atherosclerosis and restenosis following various interventions (eg, angioplasty and bypass grafting). We sought to determine whether human atherosclerosis is associated with a "resolution deficit" and whether lipoxins and resolvins influence VSMC phenotype. Here we report that plasma levels of aspirin-triggered lipoxin are significantly lower in patients with symptomatic peripheral artery disease than in healthy volunteers. Both aspirin-triggered lipoxin and resolvin E1 block platelet-derived growth factor-stimulated migration of human saphenous vein SMCs and decrease phosphorylation of the platelet-derived growth factor receptor-β. Importantly, receptors for aspirin-triggered lipoxin and resolvin E1 (ALX and ChemR23, respectively) were identified in human VSMCs. Overall, these results demonstrate that stimulatory lipid mediators confer a protective phenotypic switch in VSMCs and elucidate new functions for these mediators in the regulation of SMC biology. These results also suggest that peripheral artery disease is associated with an inflammation-resolution deficit and highlight a potential therapeutic opportunity for the regulation of vascular injury responses.
authors: Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Karen J
authors: KJ
authors: Ho
authors: Matthew
authors: M
authors: Spite
authors: Christopher D
authors: CD
authors: Owens
authors: Hope
authors: H
authors: Lancero
authors: Alex H K
authors: AH
authors: Kroemer
authors: Reena
authors: R
authors: Pande
authors: Mark A
authors: MA
authors: Creager
authors: Charles N
authors: CN
authors: Serhan
authors: Michael S
authors: MS
authors: Conte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D016022:Case-Control Studies; D002470:Cell Survival; D002633:Chemotaxis; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D044045:Lipoxins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058729:Peripheral Arterial Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012501:Saphenous Vein / Q000166:cytology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; C102741:CMKLR1 protein, human; C442142:HSH2D protein, human; D044045:Lipoxins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D015118:Eicosapentaenoic Acid; D017479:Receptors, Platelet-Derived Growth Factor; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid; D001241:Aspirin