Annexin A5 prevents post-interventional accelerated atherosclerosis development in a dose-dependent fashion in mice

Atherosclerosis. 2012 Apr;221(2):333-40. doi: 10.1016/j.atherosclerosis.2012.01.037. Epub 2012 Feb 1.

Abstract

Background: Activated cells in atherosclerotic lesions expose phosphatidylserine (PS) on their surface. Annexin A5 (AnxA5) binds to PS and is used for imaging atherosclerotic lesions. Recently, AnxA5 was shown to inhibit vascular inflammatory processes after vein grafting. Here, we report a therapeutic role for AnxA5 in post-interventional vascular remodeling in a mouse model mimicking percutaneous coronary intervention (PCI).

Methods and results: Associations between the rs4833229 (OR = 1.29 (CI 95%), p(allelic) = 0.011) and rs6830321 (OR = 1.35 (CI 95%), p(allelic) = 0.003) SNPs in the AnxA5 gene and increased restenosis-risk in patients undergoing PCI were found in the GENDER study. To evaluate AnxA5 effects on post-interventional vascular remodeling and accelerated atherosclerosis development in vivo, hypercholesterolemic ApoE(-/-) mice underwent femoral arterial cuff placement to induce intimal thickening. Dose-dependent effects were investigated after 3 days (effects on inflammation and leukocyte recruitment) or 14 days (effects on remodeling) after cuff placement. Systemically administered AnxA5 in doses of 0.1, 0.3 and 1.0mg/kg compared to vehicle reduced early leukocyte and macrophage adherence up to 48.3% (p = 0.001) and diminished atherosclerosis development by 71.2% (p = 0.012) with a reduction in macrophage/foam cell presence. Moreover, it reduced the expression of the endoplasmic reticulum stress marker GRP78/BiP, indicating lower inflammatory activity of the cells present.

Conclusions: AnxA5 SNPs could serve as markers for restenosis after PCI and AnxA5 therapeutically prevents vascular remodeling in a dose-dependent fashion, together indicating clinical potential for AnxA5 against post-interventional remodeling.

Publication types

  • Multicenter Study

MeSH terms

  • Animals
  • Annexin A5 / administration & dosage*
  • Annexin A5 / genetics
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Arterial Occlusive Diseases / etiology
  • Arterial Occlusive Diseases / immunology
  • Arterial Occlusive Diseases / pathology
  • Arterial Occlusive Diseases / prevention & control*
  • Case-Control Studies
  • Chemotaxis, Leukocyte / drug effects
  • Constriction
  • Constriction, Pathologic
  • Coronary Restenosis / genetics
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum Chaperone BiP
  • Femoral Artery / drug effects*
  • Femoral Artery / pathology
  • Femoral Artery / surgery
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Injections, Intraperitoneal
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Netherlands
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Risk Assessment
  • Risk Factors
  • Time Factors

Substances

  • Annexin A5
  • Apolipoproteins E
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Hspa5 protein, mouse