Early development of calcific aortic valve disease and left ventricular hypertrophy in a mouse model of combined dyslipidemia and type 2 diabetes mellitus.

Authors: Le Quang, KhaiBouchareb, RihabLachance, DominicLaplante, Marc AndréEl Husseini, DialaBoulanger, Marie-ChloéFournier, DominiqueFang, Xiang PingKohen Avramoglu, RitaPibarot, PhilippeDeshaies, Yves; Sweeney, Gary; Mathieu, PatrickMarette, André
Abstract: Objective—This study aimed to determine the potential impact of type 2 diabetes mellitus on left ventricular dysfunction and the development of calcified aortic valve disease using a dyslipidemic mouse model prone to developing type 2 diabetes mellitus. Approach and Results—When compared with nondiabetic LDLr-/-/ApoB100/100, diabetic LDLr-/-/ApoB100/100/IGF-II mice exhibited similar dyslipidemia and obesity but developed type 2 diabetes mellitus when fed a high-fat/sucrose/cholesterol diet for 6 months. LDLr-/-/ApoB100/100/IGF-II mice showed left ventricular hypertrophy versus C57BL6 but not LDLr-/-/ ApoB100/100 mice. Transthoracic echocardiography revealed significant reductions in both left ventricular systolic fractional shortening and diastolic function in high-fat/sucrose/cholesterol fed LDLr-/-/ApoB100/100/IGF-II mice when compared with LDLr-/-/ApoB100/100. Importantly, we found that peak aortic jet velocity was significantly increased in LDLr-/-/ApoB100/100/ IGF-II mice versus LDLr-/-/ApoB100/100 animals on the high-fat/sucrose/cholesterol diet. Microtomography scans and Alizarin red staining indicated calcification in the aortic valves, whereas electron microscopy and energy dispersive x-ray spectroscopy further revealed mineralization of the aortic leaflets and the presence of inflammatory infiltrates in diabetic mice. Studies showed upregulation of hypertrophic genes (anp, bnp, b-mhc) in myocardial tissues and of osteogenic genes (spp1, bglap, runx2) in aortic tissues of diabetic mice. Conclusions—We have established the diabetes mellitus –prone LDLr-/-/ApoB100/100/IGF-II mouse as a new model of calcified aortic valve disease. Our results are consistent with the growing body of clinical evidence that the dysmetabolic state of type 2 diabetes mellitus contributes to early mineralization of the aortic valve and calcified aortic valve disease pathogenesis.
Document Type: Article de recherche
Issue Date: 14 August 2014
Open Access Date: Restricted access
Document version: VoR
Permalink: http://hdl.handle.net/20.500.11794/6891
This document was published in: Arteriosclerosis, thrombosis, and vascular biology, Vol. 34, 2283-2291 (2014)
http://dx.doi.org/10.1161/ATVBAHA.114.304205
American Heart Association
Alternative version: 10.1161/ATVBAHA.114.304205
http://www.ncbi.nlm.nih.gov/pubmed/25231636
Collection:Articles publiés dans des revues avec comité de lecture

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