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CLINICAL RESEARCH: ATHEROSCLEROSIS

Osteocalcin Expression by Circulating Endothelial Progenitor Cells in Patients With Coronary Atherosclerosis

Mario Gössl, MD, FESC^_*, Ulrike I. Mödder, PhD, Elizabeth J. Atkinson, MS, Amir Lerman, MD, FACC^_* and Sundeep Khosla, MD^,_*

^_* Division of Cardiology, College of Medicine, Mayo Clinic, Rochester, Minnesota
Endocrine Research Unit, College of Medicine, Mayo Clinic, Rochester, Minnesota
Department of Biostatistics, College of Medicine, Mayo Clinic, Rochester, Minnesota

Manuscript received April 23, 2008; revised manuscript received July 2, 2008, accepted July 21, 2008.

^_* Reprint requests and correspondence: Dr. Sundeep Khosla, Endocrine Research Unit, College of Medicine, Mayo Clinic, 200 First Street SW, Guggenheim 7, Rochester, Minnesota 55905 (Email: khosla.sundeep{at}mayo.edu).

Objectives: This study was designed to test whether patients with coronary atherosclerosis have increases in circulating endothelial progenitor cells (EPCs) expressing an osteogenic phenotype.

Background: Increasing evidence indicates a link between bone and the vasculature, and bone marrow and circulating osteogenic cells have been identified by staining for the osteoblastic marker, osteocalcin (OCN). Endothelial progenitor cells contribute to vascular repair, but repair of vascular injury may result in calcification. Using cell surface markers (CD34, CD133, kinase insert domain receptor [KDR]) to identify EPCs, we examined whether patients with coronary atherosclerosis had increases in the percentage of EPCs expressing OCN.

Methods: We studied 72 patients undergoing invasive coronary assessment: control patients (normal coronary arteries and no endothelial dysfunction, n = 21) versus 2 groups with coronary atherosclerosis—early coronary atherosclerosis (normal coronary arteries but with endothelial dysfunction, n = 22) and late coronary atherosclerosis (severe, multivessel coronary artery disease, n = 29). Peripheral blood mononuclear cells were analyzed using flow cytometry.

Results: Compared with control patients, patients with early or late coronary atherosclerosis had significant increases (2-fold) in the percentage of CD34⁺/KDR⁺ and CD34⁺/CD133⁺/KDR⁺ cells costaining for OCN. Even larger increases were noted in the early and late coronary atherosclerosis patients in the percentage of CD34⁺/CD133^–/KDR⁺ cells costaining for OCN (5- and 2-fold, p < 0.001 and 0.05, respectively).

Conclusions: A higher percentage of EPCs express OCN in patients with coronary atherosclerosis compared with subjects with normal endothelial function and no structural coronary artery disease. These findings have potential implications for the mechanisms of vascular calcification and for the development of novel markers for coronary atherosclerosis.

Key Words: calcification • bone • atherosclerosis

Abbreviations and Acronyms   APV = average peak velocity   CAD = coronary artery disease   ECA = early coronary atherosclerosis   ELISA = enzyme-linked immunosorbent assay   EPC = endothelial progenitor cell   hMSC = human bone marrow stromal cell   hs-CRP = high sensitivity C-reactive protein   KDR = kinase insert domain receptor   LCA = late coronary atherosclerosis   MACS = magnetic activated cell sorting   MGP = matrix Gla protein   mRNA = messenger ribonucleic acid   OCN = osteocalcin   OPG = osteoprotegerin   OPN = osteopontin   PBMNC = peripheral blood mononuclear cell   RANKL = receptor activator of nuclear factor kappa B ligand   ROC = receiver-operator characteristic

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