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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1005.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

A Potential Role of the CXC Chemokine GRO in Atherosclerosis and Plaque Destabilization

Downregulatory Effects of Statins

Unni M. Breland; Bente Halvorsen; Johanna Hol; Erik Øie; Gabrielle Paulsson-Berne; Arne Yndestad; Camilla Smith; Kari Otterdal; Ulf Hedin; Torgun Wæhre; Wiggo J. Sandberg; Stig S. Frøland; Guttorm Haraldsen; Lars Gullestad; Jan K. Damås; Gøran K. Hansson; Pål Aukrust

From the Research Institute for Internal Medicine (U.M.B., B.H., A.Y., C.S., K.O., T.W., W.J.S., S.S.F., J.K.D., P.A.), the Department of Pathology (J.H., G.H.), the Department of Cardiology (E.Ø., L.G.), the Institute for Surgical Research (E.Ø.), and the Section of Clinical Immunology and Infectious Diseases (S.S.F., J.K.D., P.A.), Rikshospitalet, University of Oslo, Norway; and the Department of Surgery (U.H.) and the Department of Medicine and Centre for Molecular Medicine (G.P.-B., G.K.H.), Karolinska University Hospital, Stockholm, Sweden.

Correspondence to Unni M. Breland, Research Institute for Internal Medicine, Rikshospitalet, N-0027 Oslo, Norway. E-mail Unni.Mathilde. Breland{at}rr-research.no

Abstract

Objective— We examined the role of the CXCR2 ligand growth-related oncogene (GRO) in human atherosclerosis.

Methods and Results— GRO levels were examined by enzyme immunoassay, real-time quantitative RT-PCR, and cDNA microarrays. The in vitro effect of statins on GRO was examined in endothelial cells and THP-1 macrophages. Our main findings were: (1) GRO was among the 10 most differentially expressed transcripts comparing peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD) and healthy controls. (2) Both patients with stable (n=41) and particularly those with unstable (n=47) angina had increased plasma levels of GRO comparing controls (n=20). (3) We found increased expression of GRO within symptomatic carotid plaques, located to macrophages and endothelial cells. (4) GRO enhanced the release of matrix metalloproteinases in vascular smooth muscle cells, and increased the binding of acetylated LDL in macrophages. (5) Atorvastatin downregulated GRO levels as shown both in vitro in endothelial cells and macrophages and in vivo in PBMCs from CAD patients. (6) The effect on GRO in endothelial cells involved increased storage and reduced secretion of GRO.

Conclusions— GRO could be involved in atherogenesis and plaque destabilization, potentially contributing to inflammation, matrix degradation, and lipid accumulation within the atherosclerotic lesion.

The involvement of CXCR2 in atherogenesis is well recognized, thought to reflect interaction with interleukin-8. In the present study we found another CXCR2 ligand (ie, GRO) to be significantly upregulated in human atherosclerosis both in circulating leukocytes and within the atherosclerotic lesion, potentially promoting matrix degradation, lipid accumulation, and inflammation.

Key Words: atherosclerosis • chemokines • inflammation • endothelium