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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:2069.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Effect of Leptin on Vascular Calcification in Apolipoprotein E–Deficient Mice

Melec Zeadin; Martin Butcher; Geoff Werstuck; Mohammad Khan; Colin K. Yee; Stephen G. Shaughnessy

From the Departments of Pathology and Molecular Medicine and Medicine, McMaster University and the Henderson Research Center, Hamilton, Ontario, Canada.

Correspondence to Stephen G. Shaughnessy, PhD, Henderson Research Centre, 711 Concession Street, Hamilton, Ontario, Canada, L8V 1C3. E-mail sshaughnessy{at}thrombosis.hhscr.org

Objective— The adipocytokine leptin has been proposed to increase cardiovascular risk in both obese and diabetic individuals. In the current study, therefore, we used apoE-deficient mice to examine the effects of leptin on both lesion size and calcification.

Methods and Results— Mice were treated with once daily intraperitoneal injections of leptin (125 µg/mouse/d) for 2 months. The mice were then euthanized, and sections of the aortic root and thoracic aorta analyzed histomorphometrically. Measurements of lesion size and surface area occupied by atherosclerotic lesions did not reveal any differences between nontreated and leptin-treated animals. However, von Kossa staining of the aortic root demonstrated an 8.3±2.0-fold increase in lesion calcification as well as a 2.5±0.6-fold increase in valvular calcification in those animals treated with leptin. In addition, the percent total lesion area demonstrating ALP-positive staining was 5.4±2.1-fold greater in leptin-treated mice when compared to nontreated control mice. This increase in ALP staining was also accompanied by an increase in the expression of the osteoblast-specific markers, osteocalcin, and osteopontin.

Conclusions— Based on these observations, we conclude that leptin may increase cardiovascular risk by promoting osteogenic differentiation and thus vascular calcification.

ApoE-deficient mice placed on a high-fat diet were given daily i.p injections of saline or recombinant leptin. Leptin-treated mice demonstrated an increase in valvular and atherosclerotic lesion calcification. The increase in calcification was accompanied by an increase in the expression of osteoblast-specific markers, alkaline phosphatase, osteopontin, and osteocalcin.

Key Words: leptin • vascular calcification • atherosclerosis • osteoblasts • valvular stenosis