Chondroplastic conversion and calcification of advanced atherosclerotic lesions: The impact of bone regulatory proteins and diet

Objective. The development of advanced atherosclerotic lesions is a common pathology underlying most cardiovascular deaths. Calcification of advanced atherosclerotic lesions in humans and mice is common but the time course, cell types and mechanism(s) associated with calcification are not well understood. The ApoE-/- mouse is commonly used in atherosclerosis research and may be a promising model to study atherosclerosis associated vascular calcification. I along with several collaborators characterized the calcification of advanced atherosclerotic lesions in ApoE-/- mice. This model then was used to investigate the effect of several potential mediators of vascular calcification. The effect of the isoflavone genistein on vascular calcification was assessed using a classic feeding study approach. Using intercrosses of genetically engineered mice, the role of several bone regulatory proteins, osteoprotegerin, osteopontin and matrix-gla protein, was assessed.; Results. Calcification of advanced atherosclerotic lesions in ApoE-/- mice is preceded by the formation of fibro-fatty nodules that are populated by cells that morphologically resemble chondrocytes. These cells are temporally and spatially associated deposits of hydroxyapatite and express the same proteins as chondrocytes within developing bone.; A diet enriched with genistein reduces aortic calcium content and elevated circulating OPG. Generation of OPG-/-.apoE-/- mice indicates that OPG has a role in modulating plaque size and calcification. Because OPG-/-.ApoE-/- mice had increased lesion area and aortic calcium content. Analysis of lesion morphology indicates that OPG may act as a survival factor within the lesion.; Studies of mgp indicated that mgp inactivation increases lesion size and results in a dramatic change in lesion composition. Mgp-/-.ApoE-/- have increased chondroplastic conversion and plaque calcification at 18 weeks of age when ApoE-/- controls have less complicated and smaller fatty streaks forming. Unfortunately, there was no effect of OPN on atherosclerosis or calcification of the atherosclerotic plaques. However, there was an indication that OPN may modulate the chondroplastic conversion and calcification of the media underlying the lesion.; Conclusions. These results indicate that the ApoE-/- mouse is a viable model for studying atherosclerosis associated vascular calcification. Both diet and genetic approaches are able to alter vascular calcification in this model.