Abstract 462: Transgenic Overexpression of Tissue-nonspecific Alkaline Phosphatase in Monocytes/Macrophages Induces Calcification of Atherosclerotic Plaques

Introduction: Calcification of atherosclerotic plaques is associated with different histopathological and clinical manifestations. Microcalcification promotes inflammation and increases plaque instability, whereas macrocalcification is associated with stable fibroatheroma. The mechanisms of initiation and progression of calcification in atherosclerosis are not completely understood. Hypothesis: Upregulation of tissue-nonspecific alkaline phosphatase (TNAP) in monocytes/macrophages can lead to calcification of atherosclerotic plaques in a mouse model. Methods: TNAP overexpression was induced from a targeted transgene in Hprt locus utilizing Cre recombinase driven by monocyte-specific LyzM gene promoter. Resultant mice overexpressing TNAP in cells of monocyte/macrophage lineage (TNAP-Tg) were bred with animals bearing low density lipoprotein receptor mutation. Hypercholesterolemia was induced by feeding Paigen diet for ten weeks. Average plaque area and calcification (area %) were determined from histological sections of the aortic root (5-10 sections/sample). Blood flow velocity in the ascending aorta and left ventricular function were assessed by echocardiography. Results: In the absence of atherosclerosis, no appreciable soft tissue calcification was observed in TNAP-Tg animals (n=2). During progression of atherosclerosis, calcification was detected in the aortic root lesions of TNAP-Tg mice (4.85% of total plaque area) in significant excess compared to controls (0.02%, p Conclusions: We developed an animal model in which the interaction between early calcium deposition inside atherosclerotic lesions and the stability of such lesions can be studied experimentally.