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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.

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  • Authors+Show Affiliations

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    Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany. korkmaz@uni-heidelberg.de.

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    Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.

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    Heart and Vascular Center, Semmelweis University, Városmajor u. 68, Budapest, 1122, Hungary.

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    Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.

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    Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 671, 69120, Heidelberg, Germany.

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    Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.

    ,

    Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.

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    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.

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    Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.

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    Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

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    Hamamatsu Tissue Imaging and Analysis Center (TIGA), Bioquant, University of Heidelberg, 69120, Heidelberg, Germany. Steinbeis Transfer Center for Medical Systems Biology, 69124, Heidelberg, Germany.

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    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.

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    Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.

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    Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.

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    Molecular and Translational Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

    ,

    Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.

    Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.

    Source

    Cardiovascular diabetology 15: 2016 May 06 pg 75

    MeSH

    Administration, Oral
    Animals
    Aspirin
    Diabetes Mellitus, Experimental
    Diabetes Mellitus, Type 2
    Diabetic Cardiomyopathies
    Heart Ventricles
    Male
    Proto-Oncogene Proteins c-akt
    Rats
    Rats, Zucker
    Signal Transduction
    Zinc

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    27153943

    Citation

    Korkmaz-Icöz, Sevil, et al. "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." Cardiovascular Diabetology, vol. 15, 2016, p. 75.
    Korkmaz-Icöz S, Al Said S, Radovits T, et al. 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. Cardiovasc Diabetol. 2016;15:75.
    Korkmaz-Icöz, S., Al Said, S., Radovits, T., Li, S., Brune, M., Hegedűs, P., ... Szabó, G. (2016). 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. Cardiovascular Diabetology, 15, p. 75. doi:10.1186/s12933-016-0383-8.
    Korkmaz-Icöz S, et al. 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. Cardiovasc Diabetol. 2016 May 6;15:75. PubMed PMID: 27153943.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. AU - Korkmaz-Icöz,Sevil, AU - Al Said,Samer, AU - Radovits,Tamás, AU - Li,Shiliang, AU - Brune,Maik, AU - Hegedűs,Péter, AU - Atmanli,Ayhan, AU - Ruppert,Mihály, AU - Brlecic,Paige, AU - Lehmann,Lorenz Heyne, AU - Lahrmann,Bernd, AU - Grabe,Niels, AU - Yoshikawa,Yutaka, AU - Yasui,Hiroyuki, AU - Most,Patrick, AU - Karck,Matthias, AU - Szabó,Gábor, Y1 - 2016/05/06/ PY - 2015/10/30/received PY - 2016/04/05/accepted PY - 2016/5/8/entrez PY - 2016/5/8/pubmed PY - 2017/1/4/medline KW - Cardiac function KW - Diabetic cardiomyopathy KW - Type-2 diabetes mellitus KW - Zinc-aspirin complex SP - 75 EP - 75 JF - Cardiovascular diabetology JO - Cardiovasc Diabetol VL - 15 N2 - 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. SN - 1475-2840 UR - https://www.unboundmedicine.com/medline/citation/27153943/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_ L2 - https://cardiab.biomedcentral.com/articles/10.1186/s12933-016-0383-8 DB - PRIME DP - Unbound Medicine ER -