Abstract 375: Alkaline Phosphatase-driven Vascular Calcification Interacts with Hypercholesterolemia and Leads to Severe Coronary Atherosclerosis and Heart Failure in Mice
Objective: Asymptomatic calcification of coronary arteries can independently predict future coronary heart disease. It is not yet clear, however, whether the temporal presence of calcification in coronary arteries is pathogenic. We have recently demonstrated that upregulation of tissue-nonspecific alkaline phosphatase (TNAP) in vascular smooth muscle cells in vivo is sufficient to induce medial calcification. The purpose of this study was to test the hypothesis that TNAP-driven intimal calcification can promote coronary atherosclerosis in a mouse model.
Methods: TNAP was overexpressed in endothelial cells in wild type mice and in mice harboring “wicked high cholesterol” (WHC) mutation in the low density lipoprotein receptor. Hypercholesterolemia was induced in WHC mice by feeding an atherogenic diet. Physiological, histological, and biochemical data were collected longitudinally.
Results: In the absence of hypercholesterolemia, pan-endothelial overexpression of TNAP induced systemic generalized arterial calcification with normal calcium and phosphate metabolism, but with elevated blood pressure and physiological left ventricular (LV) hypertrophy. Calcific nodules first appear in the arterial intima and expand into the arterial media. Combined with the WHC mutation and 6-8 weeks on atherogenic diet, TNAP-driven arterial calcification led to severe atherosclerosis with 100% morbidity characterized by occlusive coronary artery disease (histologically), pathological cardiac hypertrophy with LV dilation, and reduced cardiac ejection fraction (EF).
Conclusions: Arterial calcification promotes lipid deposition and is pathogenic when cholesterol is elevated due to genetic and dietary causes.
Author Disclosures: A.Y. Savinov: None. M.C. Yadav: None. J. Millán: None. O.V. Savinova: None.
- © 2015 by American Heart Association, Inc.