Enhanced expression of the homeostatic chemokines CCL19 and CCL21 in clinical and experimental atherosclerosis: possible pathogenic role in plaque destabilization

Arterioscler Thromb Vasc Biol. 2007 Mar;27(3):614-20. doi: 10.1161/01.ATV.0000255581.38523.7c. Epub 2006 Dec 14.

Abstract

Objective: Based on their role in T-cell homing into nonlymphoid tissue, we examined the role of the homeostatic chemokines CCL19 and CCL21 and their common receptor CCR7 in coronary artery disease (CAD).

Methods and results: We performed studies in patients with stable (n=40) and unstable (n=40) angina and healthy controls (n=20), in vitro studies in T-cells and macrophages, and studies in apolipoprotein-E-deficient (ApoE-/-) mice and human atherosclerotic carotid plaques. We found increased levels of CCL19 and CCL21 within the atherosclerotic lesions of the ApoE-/- mice, in human atherosclerotic carotid plaques, and in plasma of CAD patients. Whereas strong CCR7 expression was seen in T-cells from murine and human atherosclerotic plaques, circulating T-cells from angina patients showed decreased CCR7 expression. CCL19 and CCL21 promoted an inflammatory phenotype in T-cells and macrophages and increased matrix metalloproteinase (MMP) and tissue factor levels in the latter cell type. Although aggressive statin therapy increased CCR7 and decreased CCL19/CCL21 levels in peripheral blood from CAD patients, conventional therapy did not.

Conclusions: The abnormal regulation of CCL19 and CCL21 and their common receptor in atherosclerosis could contribute to disease progression by recruiting T-cells and macrophages to the atherosclerotic lesions and by promoting inflammatory responses in these cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angioplasty, Balloon, Coronary / methods
  • Animals
  • Apolipoproteins E / deficiency
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control
  • Atorvastatin
  • Biopsy, Needle
  • Cells, Cultured
  • Chemokine CCL19
  • Chemokine CCL21
  • Chemokines, CC / genetics
  • Chemokines, CC / metabolism*
  • Coronary Disease / blood*
  • Coronary Disease / drug therapy*
  • Coronary Disease / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Gene Expression Regulation
  • Heptanoic Acids / therapeutic use*
  • Humans
  • Immunohistochemistry
  • In Vitro Techniques
  • Leukocytes, Mononuclear
  • Mice
  • Mice, Transgenic
  • Prognosis
  • Pyrroles / therapeutic use*
  • RNA, Messenger / analysis
  • Receptors, CCR7
  • Receptors, Chemokine / metabolism
  • Reference Values
  • Risk Factors
  • Sensitivity and Specificity
  • Simvastatin / therapeutic use*
  • Treatment Outcome

Substances

  • Apolipoproteins E
  • CCL19 protein, human
  • CCL21 protein, human
  • CCR7 protein, human
  • Ccl19 protein, mouse
  • Ccl21c protein, mouse
  • Ccr7 protein, mouse
  • Chemokine CCL19
  • Chemokine CCL21
  • Chemokines, CC
  • Heptanoic Acids
  • Pyrroles
  • RNA, Messenger
  • Receptors, CCR7
  • Receptors, Chemokine
  • Atorvastatin
  • Simvastatin