title: Combination of cadmium and high cholesterol levels as a risk factor for heart fibrosis.
abstract: The deleterious effects of increased cadmium (Cd) serum levels on the cardiovascular system are proven by epidemiological and basic science studies. Cd exposure of animals and humans is known to impair myocardial function, possibly leading to heart failure. This study aims at investigating the effect of Cd treatment on the cardiac system with emphasis on the combined effect of Cd and high serum cholesterol levels as an important cardiovascular risk factor. Detailed analyses of Cd-induced effects on the heart of ApoE-/- mice fed a high fat diet (HFD), ApoE-/- mice fed a normal diet (ND), and C57BL/6J mice fed a ND revealed proinflammatory and fibrotic changes in the presence of cellular hypertrophy but in the absence of organ hypertrophy. Hypercholesterolemia in ApoE-/- mice alone and in combination with Cd treatment resulted in significant cardiomyocyte cell death. Based on further analyses of heart sections, we conclude that severe hypercholesterolemia in combination with ApoE-/- genotype as well as Cd treatment results in necrotic cardiomyocyte death. These data were supported by in vitro experiments showing a Cd-induced depolarization of the mitochondrial membrane and the permeabilization of the plasma membrane arguing for the occurrence of Cd-induced necrotic cell death. In summary, we were able to show for the first time that the combination of high cholesterol and Cd levels increase the risk for heart failure through cardiac fibrosis. This observation could in part be explained by the dramatically increased deposition of Cd in the hearts of ApoE-/- mice fed a HFD.
authors.affiliation: *Cardiac Surgery Research Laboratory, Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria and Cardiac Surgery Research Laboratory Innsbruck, University Clinic for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Adrian
authors.initials: A
authors.lastname: Türkcan
authors.affiliation: *Cardiac Surgery Research Laboratory, Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria and Cardiac Surgery Research Laboratory Innsbruck, University Clinic for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Scharinger
authors.affiliation: *Cardiac Surgery Research Laboratory, Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria and Cardiac Surgery Research Laboratory Innsbruck, University Clinic for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Grabmann
authors.affiliation: *Cardiac Surgery Research Laboratory, Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria and Cardiac Surgery Research Laboratory Innsbruck, University Clinic for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: *Cardiac Surgery Research Laboratory, Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria and Cardiac Surgery Research Laboratory Innsbruck, University Clinic for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Günther
authors.initials: G
authors.lastname: Laufer
authors.affiliation: *Cardiac Surgery Research Laboratory, Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria and Cardiac Surgery Research Laboratory Innsbruck, University Clinic for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Bernhard
authors.affiliation: *Cardiac Surgery Research Laboratory, Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria and Cardiac Surgery Research Laboratory Innsbruck, University Clinic for Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria Barbara.Messner@meduniwien.ac.at.
authors.forename: Barbara
authors.initials: B
authors.lastname: Messner
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001822:Body Burden; D019256:Cadmium Chloride; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications* / Q000235:genetics; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis; D016212:Transforming Growth Factor beta / Q000097:blood; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D015415:Biomarkers; D019256:Cadmium Chloride; D018932:Chemokine CCL2; D002784:Cholesterol; D016212:Transforming Growth Factor beta; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C491768:Ccl2 protein, mouse
keywords: HL-1; cardiomyocyte hypertrophy; cell death; cholesterol; macrophages