title: Oral treatment with a zinc complex of acetylsalicylic acid prevents diabetic cardiomyopathy in a rat model of type-2 diabetes: activation of the Akt pathway.
abstract: BACKGROUND
  Type-2 diabetics have an increased risk of cardiomyopathy, and heart failure is a major cause of death among these patients. Growing evidence indicates that proinflammatory cytokines may induce the development of insulin resistance, and that anti-inflammatory medications may reverse this process. We investigated the effects of the oral administration of zinc and acetylsalicylic acid, in the form of bis(aspirinato)zinc(II)-complex Zn(ASA)2, on different aspects of cardiac damage in Zucker diabetic fatty (ZDF) rats, an experimental model of type-2 diabetic cardiomyopathy.
  
  
  METHODS
  Nondiabetic control (ZL) and ZDF rats were treated orally with vehicle or Zn(ASA)2 for 24 days. At the age of 29-30 weeks, the electrical activities, left-ventricular functional parameters and left-ventricular wall thicknesses were assessed. Nitrotyrosine immunohistochemistry, TUNEL-assay, and hematoxylin-eosin staining were performed. The protein expression of the insulin-receptor and PI3K/AKT pathway were quantified by Western blot.
  
  
  RESULTS
  Zn(ASA)2-treatment significantly decreased plasma glucose concentration in ZDF rats (39.0 ± 3.6 vs 49.4 ± 2.8 mM, P < 0.05) while serum insulin-levels were similar among the groups. Data from cardiac catheterization showed that Zn(ASA)2 normalized the increased left-ventricular diastolic stiffness (end-diastolic pressure-volume relationship: 0.064 ± 0.008 vs 0.084 ± 0.014 mmHg/µl; end-diastolic pressure: 6.5 ± 0.6 vs 7.9 ± 0.7 mmHg, P < 0.05). Furthermore, ECG-recordings revealed a restoration of prolonged QT-intervals (63 ± 3 vs 83 ± 4 ms, P < 0.05) with Zn(ASA)2. Left-ventricular wall thickness, assessed by echocardiography, did not differ among the groups. However histological examination revealed an increase in the cardiomyocytes' transverse cross-section area in ZDF compared to the ZL rats, which was significantly decreased after Zn(ASA)2-treatment. Additionally, a significant fibrotic remodeling was observed in the diabetic rats compared to ZL rats, and Zn(ASA)2-administered ZDF rats showed a similar collagen content as ZL animals. In diabetic hearts Zn(ASA)2 significantly decreased DNA-fragmentation, and nitro-oxidative stress, and up-regulated myocardial phosphorylated-AKT/AKT protein expression. Zn(ASA)2 reduced cardiomyocyte death in a cellular model of oxidative stress. Zn(ASA)2 had no effects on altered myocardial CD36, GLUT-4, and PI3K protein expression.
  
  
  CONCLUSIONS
  We demonstrated that treatment of type-2 diabetic rats with Zn(ASA)2 reduced plasma glucose-levels and prevented diabetic cardiomyopathy. The increased myocardial AKT activation could, in part, help to explain the cardioprotective effects of Zn(ASA)2. The oral administration of Zn(ASA)2 may have therapeutic potential, aiming to prevent/treat cardiac complications in type-2 diabetic patients.
authors.affiliation: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany. korkmaz@uni-heidelberg.de.
authors.forename: Sevil
authors.initials: S
authors.lastname: Korkmaz-Icöz
authors.affiliation: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
authors.forename: Samer
authors.initials: S
authors.lastname: Al Said
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68, Budapest, 1122, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Radovits
authors.affiliation: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 671, 69120, Heidelberg, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Brune
authors.affiliation: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
authors.forename: Péter
authors.initials: P
authors.lastname: Hegedűs
authors.affiliation: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
authors.forename: Ayhan
authors.initials: A
authors.lastname: Atmanli
authors.affiliation: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.|Heart and Vascular Center, Semmelweis University, Városmajor u. 68, Budapest, 1122, Hungary.
authors.forename: Mihály
authors.initials: M
authors.lastname: Ruppert
authors.affiliation: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
authors.forename: Paige
authors.initials: P
authors.lastname: Brlecic
authors.affiliation: Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Lorenz Heyne
authors.initials: LH
authors.lastname: Lehmann
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center (TIGA), Bioquant, University of Heidelberg, 69120, Heidelberg, Germany.|Steinbeis Transfer Center for Medical Systems Biology, 69124, Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lahrmann
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center (TIGA), Bioquant, University of Heidelberg, 69120, Heidelberg, Germany.|Steinbeis Transfer Center for Medical Systems Biology, 69124, Heidelberg, Germany.|Department of Medical Oncology, National Center for Tumor Diseases, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshikawa
authors.affiliation: Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasui
authors.affiliation: Molecular and Translational Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
authors.affiliation: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.affiliation: Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects*; D015032:Zinc / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D015032:Zinc; D001241:Aspirin
keywords: Cardiac function; Diabetic cardiomyopathy; Type-2 diabetes mellitus; Zinc-aspirin complex