Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:489-494
Published online before print January 30, 2003, doi: 10.1161/01.ATV.0000059406.92165.31
Published online before print January 30, 2003, doi: 10.1161/01.ATV.0000059406.92165.31
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© 2003 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Osteo/Chondrocytic Transcription Factors and Their Target Genes Exhibit Distinct Patterns of Expression in Human Arterial Calcification
From the Department of Medicine, A.C.C.I., Level 6, Box 110 Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ UK.
Correspondence to Dr. Catherine Shanahan, Department of Medicine, Addenbrooke’s Centre for Clinical Investigation, Box 110, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ UK. E-mail cs131{at}mole.bio.cam.ac.uk
Objective— Mineralization-regulating proteins are found deposited at sites of vascular calcification. However, the relationship between the onset of calcification in vivo and the expression of genes encoding mineralization-regulating proteins is unknown. This study aimed to determine the temporal and spatial pattern of expression of key bone and cartilage proteins as atherosclerotic calcification progresses.
Methods and Results— Using reverse transcription-polymerase chain reaction on a panel of noncalcified and calcified human arterial samples, two classes of proteins could be identified: (1) Matrix Gla protein, osteonectin, osteoprotegerin, and aggrecan were constitutively expressed by vascular smooth muscle cells (VSMCs) in the normal vessel media but downregulated in calcified arteries whereas (2) alkaline phosphatase, bone sialoprotein, osteocalcin, and collagen II were expressed predominantly in the calcified vessel together with Cbfa1, Msx2, and Sox9, transcription factors that regulate expression of these genes. In the calcified plaque in situ hybridization identified subsets of VSMCs expressing osteoblast and chondrocyte-like gene expression profiles whereas osteoclast-like macrophages were present around sites of calcification.
Conclusions— These observations suggest a sequence of molecular events in vascular calcification beginning with the loss of expression by VSMCs, of constitutive inhibitory proteins, and ending with expression by VSMCs and macrophages of chondrocytic, osteoblastic, and osteoclastic-associated proteins that orchestrate the calcification process.
Key Words: calcification • atherosclerosis • osteoblast • cartilage • vascular smooth muscle cell • macrophage
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