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

Arterioscler Thromb Vasc Biol. 2014 Oct;34(10):2283-91. doi: 10.1161/ATVBAHA.114.304205. Epub 2014 Aug 14.

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(-/-)/ApoB(100/100), diabetic LDLr(-/-)/ApoB(100/100)/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(-/-)/ApoB(100/100)/IGF-II mice showed left ventricular hypertrophy versus C57BL6 but not LDLr(-/-)/ApoB(100/100) mice. Transthoracic echocardiography revealed significant reductions in both left ventricular systolic fractional shortening and diastolic function in high-fat/sucrose/cholesterol fed LDLr(-/-)/ApoB(100/100)/IGF-II mice when compared with LDLr(-/-)/ApoB(100/100). Importantly, we found that peak aortic jet velocity was significantly increased in LDLr(-/-)/ApoB(100/100)/IGF-II mice versus LDLr(-/-)/ApoB(100/100) 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(-/-)/ApoB(100/100)/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.

Keywords: aortic valve stenosis; diabetes mellitus, type 2; inflammation; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Valve / metabolism
  • Aortic Valve / pathology*
  • Aortic Valve / physiopathology
  • Aortic Valve Stenosis / diagnosis
  • Aortic Valve Stenosis / etiology*
  • Aortic Valve Stenosis / genetics
  • Aortic Valve Stenosis / metabolism
  • Aortic Valve Stenosis / physiopathology
  • Apolipoprotein B-100
  • Apolipoproteins B / genetics
  • Apolipoproteins B / metabolism
  • Calcinosis / diagnosis
  • Calcinosis / etiology*
  • Calcinosis / genetics
  • Calcinosis / metabolism
  • Calcinosis / physiopathology
  • Cholesterol, Dietary
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diet, High-Fat
  • Dietary Sucrose
  • Disease Models, Animal
  • Dyslipidemias / complications*
  • Dyslipidemias / genetics
  • Dyslipidemias / metabolism
  • Gene Expression Regulation
  • Genotype
  • Hypertrophy, Left Ventricular / diagnosis
  • Hypertrophy, Left Ventricular / etiology*
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / physiopathology
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Time Factors
  • Ventricular Dysfunction, Left / etiology
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Function, Left

Substances

  • Apob protein, mouse
  • Apolipoprotein B-100
  • Apolipoproteins B
  • Cholesterol, Dietary
  • Dietary Sucrose
  • IGF2 protein, mouse
  • Receptors, LDL
  • Insulin-Like Growth Factor II

Supplementary concepts

  • Aortic Valve, Calcification of