title: Early development of calcific aortic valve disease and left ventricular hypertrophy in a mouse model of combined dyslipidemia and type 2 diabetes mellitus.
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.
  
  
  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.
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Khai
authors.initials: K
authors.lastname: Le Quang
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Rihab
authors.initials: R
authors.lastname: Bouchareb
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Dominic
authors.initials: D
authors.lastname: Lachance
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Laplante
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Diala
authors.initials: D
authors.lastname: El Husseini
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Marie-Chloé
authors.initials: MC
authors.lastname: Boulanger
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Dominique
authors.initials: D
authors.lastname: Fournier
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Xiang Ping
authors.initials: XP
authors.lastname: Fang
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Rita Kohen
authors.initials: RK
authors.lastname: Avramoglu
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Yves
authors.initials: Y
authors.lastname: Deshaies
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Gary
authors.initials: G
authors.lastname: Sweeney
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
authors.affiliation: From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.). andre.marette@criucpq.ulaval.ca.
authors.forename: André
authors.initials: A
authors.lastname: Marette
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001024:Aortic Valve Stenosis / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D002114:Calcinosis / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002791:Cholesterol, Dietary; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002791:Cholesterol, Dietary; D019422:Dietary Sucrose; C513121:IGF2 protein, mouse; D011973:Receptors, LDL; D007335:Insulin-Like Growth Factor II
keywords: aortic valve stenosis; diabetes mellitus, type 2; inflammation; obesity