title: Metallothioneins 1 and 2 Modulate Inflammation and Support Remodeling in Ischemic Cardiomyopathy in Mice.
abstract: Aims. Repetitive brief ischemia and reperfusion (I/R) is associated with left ventricular dysfunction during development of ischemic cardiomyopathy. We investigated the role of zinc-donor proteins metallothionein MT1 and MT2 in a closed-chest murine model of I/R. Methods. Daily 15-minute LAD-occlusion was performed for 1, 3, and 7 days in SV129 (WT)- and MT1/2 knockout (MT(-/-))-mice (n = 8-10/group). Hearts were examined with M-mode echocardiography and processed for histological and mRNA studies. Results. Expression of MT1/2 mRNA was transiently induced during repetitive I/R in WT-mice, accompanied by a transient inflammation, leading to interstitial fibrosis with left ventricular dysfunction without infarction. In contrast, MT(-/-)-hearts presented with enhanced apoptosis and small infarctions leading to impaired global and regional pump function. Molecular analysis revealed maladaptation of myosin heavy chain isoforms and antioxidative enzymes in MT1/2(-/-)-hearts. Despite their postponed chemokine induction we found a higher total neutrophil density and macrophage infiltration in small infarctions in MT(-/-)-hearts. Subsequently, higher expression of osteopontin 1 and tenascin C was associated with increased myofibroblast density resulting in predominately nonreversible fibrosis and adverse remodeling in MT1/2(-/-)-hearts. Conclusion. Cardioprotective effects of MT1/2 seem to be exerted via modulation of contractile elements, antioxidative enzymes, inflammatory response, and myocardial remodeling.
authors.affiliation: Department of Cardiac Surgery, University Clinical Center, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Georg D
authors.identifier: 0000-0002-0310-6236
authors.initials: GD
authors.lastname: Duerr
authors.affiliation: Department of Anesthesiology, University Clinical Center, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dewald
authors.affiliation: Department of Ophthalmology, University Clinical Center, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Eva J
authors.initials: EJ
authors.lastname: Schmitz
authors.affiliation: Department of Cardiac Surgery, University Clinical Center, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Luise
authors.initials: L
authors.lastname: Verfuerth
authors.affiliation: Department of General, Visceral, Thoracic and Vascular Surgery, University Clinical Center, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Keppel
authors.affiliation: Department of Cardiac Surgery, University Clinical Center, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Peigney
authors.affiliation: Department of Medicine II-Cardiology, University Clinical Center, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ghanem
authors.affiliation: Department of Cardiac Surgery, University Clinical Center, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Welz
authors.affiliation: Department of Cardiac Surgery, University Clinical Center, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dewald
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D009202:Cardiomyopathies / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000276:immunology / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053495:Osteopontin / Q000378:metabolism; D019063:Tenascin / Q000378:metabolism
chemical_list: C491054:Mt2 protein, mouse; D019063:Tenascin; D053495:Osteopontin; D008668:Metallothionein