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

Sevil Korkmaz-Icöz, Samer Al Said, T. Radovits, Shiliang Li, Maik Brune, Péter Hegedus, Ayhan Atmanli, Mihály Ruppert, Paige Brlecic, Lorenz Heyne Lehmann, Bernd Lahrmann, Niels Grabe, Yutaka Yoshikawa, Hiroyuki Yasui, Patrick Most, Matthias Karck, G. Szabó

Research output: Contribution to journalArticle

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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 ±2.8mM, P2 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.

Original languageEnglish
Article number75
Pages (from-to)1-16
Number of pages16
JournalCardiovascular Diabetology
Volume15
Issue number1
DOIs
Publication statusPublished - May 6 2016

Fingerprint

Diabetic Cardiomyopathies
Type 2 Diabetes Mellitus
Aspirin
Zinc
Therapeutics
Phosphatidylinositol 3-Kinases
Cardiac Myocytes
Oral Administration
Oxidative Stress
Glucose Transporter Type 4
Blood Pressure
Glucose
Insulin Receptor
In Situ Nick-End Labeling
DNA Fragmentation
Hematoxylin
Eosine Yellowish-(YS)
Cardiomyopathies
Echocardiography
Insulin Resistance

Keywords

  • Cardiac function
  • Diabetic cardiomyopathy
  • Type-2 diabetes mellitus
  • Zinc-aspirin complex

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Korkmaz-Icöz, Sevil; Al Said, Samer; Radovits, T.; Li, Shiliang; Brune, Maik; Hegedus, Péter; Atmanli, Ayhan; Ruppert, Mihály; Brlecic, Paige; Lehmann, Lorenz Heyne; Lahrmann, Bernd; Grabe, Niels; Yoshikawa, Yutaka; Yasui, Hiroyuki; Most, Patrick; Karck, Matthias; Szabó, G.

In: Cardiovascular Diabetology, Vol. 15, No. 1, 75, 06.05.2016, p. 1-16.

Research output: Contribution to journalArticle

Korkmaz-Icöz, S, Al Said, S, Radovits, T, Li, S, Brune, M, Hegedus, P, Atmanli, A, Ruppert, M, Brlecic, P, Lehmann, LH, Lahrmann, B, Grabe, N, Yoshikawa, Y, Yasui, H, Most, P, Karck, M & 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, vol. 15, no. 1, 75, pp. 1-16. https://doi.org/10.1186/s12933-016-0383-8
Korkmaz-Icöz, Sevil ; Al Said, Samer ; Radovits, T. ; Li, Shiliang ; Brune, Maik ; Hegedus, Péter ; Atmanli, Ayhan ; Ruppert, Mihály ; Brlecic, Paige ; Lehmann, Lorenz Heyne ; Lahrmann, Bernd ; Grabe, Niels ; Yoshikawa, Yutaka ; Yasui, Hiroyuki ; Most, Patrick ; Karck, Matthias ; Szabó, G. / 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. In: Cardiovascular Diabetology. 2016 ; Vol. 15, No. 1. pp. 1-16.
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TY - JOUR

T1 - Oral treatment with a zinc complex of acetylsalicylic acid prevents diabetic cardiomyopathy in a rat model of type-2 diabetes

T2 - Activation of the Akt pathway

AU - Korkmaz-Icöz, Sevil

AU - Al Said, Samer

AU - Radovits, T.

AU - Li, Shiliang

AU - Brune, Maik

AU - Hegedus, 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, G.

PY - 2016/5/6

Y1 - 2016/5/6

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 ±2.8mM, P2 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.

AB - 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 ±2.8mM, P2 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.

KW - Cardiac function

KW - Diabetic cardiomyopathy

KW - Type-2 diabetes mellitus

KW - Zinc-aspirin complex

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