Annexin A5 therapy attenuates vascular inflammation and remodeling and improves endothelial function in mice.
OBJECTIVE
Annexin A5 (AnxA5) has antithrombotic, antiapoptotic, and antiinflammatory properties; we investigated its effectiveness against vascular inflammation, remodeling, and dysfunction in accelerated atherosclerosis.


RESULTS
AnxA5 (1 mg/kg per day or vehicle) was investigated in vascular injury models in hypercholesterolemic apolipoprotein E (ApoE)3*Leiden mice. AnxA5 treatment reduced adhesion and infiltration of leukocytes by 71% to 69% (P=0.015, P=0.031) and macrophages by 51% to 87% (P=0.014, P=0.018), as well as monocyte chemotactic protein-1 and tumor necrosis factor-α expression in a femoral artery inflammation model (perivascular cuff for 3 days), indicating reduced vascular inflammation. In a vein graft model, 28 days of AnxA5 treatment reduced vein graft thickening (48%; P=0.006) and leukocyte infiltration (46%; P=0.003). In these mice, reduced plasma concentrations of IFN-γ (-72%; P=0.040), granulocyte colony-stimulating factor (-41%; P=0.010), and macrophage inflammatory protein-1β (MIP-1β) (-66%; P=0.020) were measured, indicating reduced systemic inflammation. An in vitro endothelial cell model shows the importance of AnxA5's anticoagulant properties in reducing vascular inflammation. Endothelium-mediated dilatation in hypercholesterolemic ApoE((-/-)) mice was improved by 3 days of AnxA5 treatment, shown by improved systolic and diastolic blood pressure reductions in response to metacholine, which could be abolished by l-Nitro-Arginine-Methyl Ester (l-NAME), indicating nitric oxide involvement.


CONCLUSIONS
AnxA5 reduced local vascular and systemic inflammation and vascular remodeling and improved vascular function, indicating that it has a therapeutic potential against atherosclerotic cardiovascular diseases.
Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
Mark M
MM
Ewing
Margreet R
MR
de Vries
Mariette
M
Nordzell
Knut
K
Pettersson
Hetty C
HC
de Boer
Anton Jan
AJ
van Zonneveld
Johan
J
Frostegård
J Wouter
JW
Jukema
Paul H A
PH
Quax
D000818:Animals; D017304:Annexin A5 / Q000008:administration & dosage / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006083:Graft Occlusion, Vascular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood; D007274:Injections, Intraperitoneal; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism; D013997:Time Factors; D014654:Vascular Patency / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014680:Veins / Q000637:transplantation
D017304:Annexin A5; D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D009569:Nitric Oxide