The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus

Csaba Mátyás, Balázs Tamás Németh, A. Oláh, László Hidi, Ede Birtalan, Dalma Kellermayer, Mihály Ruppert, Sevil Korkmaz-Icöz, Gábor Kökény, Eszter Mária Horváth, G. Szabó, B. Merkely, T. Radovits

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: Diabetes mellitus (DM) leads to the development of diabetic cardiomyopathy, which is associated with altered nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signalling. Cardioprotective effects of elevated intracellular cGMP-levels have been described in different heart diseases. In the current study we aimed at investigating the effects of pharmacological activation of sGC in diabetic cardiomyopathy. Methods: Type-1 DM was induced in rats by streptozotocin. Animals were treated either with the sGC activator cinaciguat (10mg/kg/day) or with placebo orally for 8weeks. Left ventricular (LV) pressure-volume (P-V) analysis was used to assess cardiac performance. Additionally, gene expression (qRT-PCR) and protein expression analysis (western blot) were performed. Cardiac structure, markers of fibrotic remodelling and DNA damage were examined by histology, immunohistochemistry and TUNEL assay, respectively. Results: DM was associated with deteriorated cGMP signalling in the myocardium (elevated phosphodiesterase-5 expression, lower cGMP-level and impaired PKG activity). Cardiomyocyte hypertrophy, fibrotic remodelling and DNA fragmentation were present in DM that was associated with impaired LV contractility (preload recruitable stroke work (PRSW): 49.5±3.3 vs. 83.0±5.5mmHg, P

Original languageEnglish
Article number145
JournalCardiovascular Diabetology
Volume14
Issue number1
DOIs
Publication statusPublished - Oct 31 2015

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Cyclic GMP
Type 1 Diabetes Mellitus
Diabetic Cardiomyopathies
Diabetes Mellitus
Type 5 Cyclic Nucleotide Phosphodiesterases
In Situ Nick-End Labeling
Ventricular Pressure
DNA Fragmentation
Streptozocin
Cardiac Myocytes
Hypertrophy
DNA Damage
Heart Diseases
Myocardium
Histology
Nitric Oxide
Western Blotting
Immunohistochemistry
Stroke
Placebos

Keywords

  • Apoptosis
  • CGMP
  • Diabetic complications
  • Fibrosis
  • Heart failure
  • Insulin dependent diabetes mellitus
  • Oxidative stress
  • PDE-5
  • Pressure-volume relationship
  • SGC activator

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus. / Mátyás, Csaba; Németh, Balázs Tamás; Oláh, A.; Hidi, László; Birtalan, Ede; Kellermayer, Dalma; Ruppert, Mihály; Korkmaz-Icöz, Sevil; Kökény, Gábor; Horváth, Eszter Mária; Szabó, G.; Merkely, B.; Radovits, T.

In: Cardiovascular Diabetology, Vol. 14, No. 1, 145, 31.10.2015.

Research output: Contribution to journalArticle

Mátyás, Csaba ; Németh, Balázs Tamás ; Oláh, A. ; Hidi, László ; Birtalan, Ede ; Kellermayer, Dalma ; Ruppert, Mihály ; Korkmaz-Icöz, Sevil ; Kökény, Gábor ; Horváth, Eszter Mária ; Szabó, G. ; Merkely, B. ; Radovits, T. / The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus. In: Cardiovascular Diabetology. 2015 ; Vol. 14, No. 1.
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AU - Németh, Balázs Tamás

AU - Oláh, A.

AU - Hidi, László

AU - Birtalan, Ede

AU - Kellermayer, Dalma

AU - Ruppert, Mihály

AU - Korkmaz-Icöz, Sevil

AU - Kökény, Gábor

AU - Horváth, Eszter Mária

AU - Szabó, G.

AU - Merkely, B.

AU - Radovits, T.

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N2 - Background: Diabetes mellitus (DM) leads to the development of diabetic cardiomyopathy, which is associated with altered nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signalling. Cardioprotective effects of elevated intracellular cGMP-levels have been described in different heart diseases. In the current study we aimed at investigating the effects of pharmacological activation of sGC in diabetic cardiomyopathy. Methods: Type-1 DM was induced in rats by streptozotocin. Animals were treated either with the sGC activator cinaciguat (10mg/kg/day) or with placebo orally for 8weeks. Left ventricular (LV) pressure-volume (P-V) analysis was used to assess cardiac performance. Additionally, gene expression (qRT-PCR) and protein expression analysis (western blot) were performed. Cardiac structure, markers of fibrotic remodelling and DNA damage were examined by histology, immunohistochemistry and TUNEL assay, respectively. Results: DM was associated with deteriorated cGMP signalling in the myocardium (elevated phosphodiesterase-5 expression, lower cGMP-level and impaired PKG activity). Cardiomyocyte hypertrophy, fibrotic remodelling and DNA fragmentation were present in DM that was associated with impaired LV contractility (preload recruitable stroke work (PRSW): 49.5±3.3 vs. 83.0±5.5mmHg, P

AB - Background: Diabetes mellitus (DM) leads to the development of diabetic cardiomyopathy, which is associated with altered nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signalling. Cardioprotective effects of elevated intracellular cGMP-levels have been described in different heart diseases. In the current study we aimed at investigating the effects of pharmacological activation of sGC in diabetic cardiomyopathy. Methods: Type-1 DM was induced in rats by streptozotocin. Animals were treated either with the sGC activator cinaciguat (10mg/kg/day) or with placebo orally for 8weeks. Left ventricular (LV) pressure-volume (P-V) analysis was used to assess cardiac performance. Additionally, gene expression (qRT-PCR) and protein expression analysis (western blot) were performed. Cardiac structure, markers of fibrotic remodelling and DNA damage were examined by histology, immunohistochemistry and TUNEL assay, respectively. Results: DM was associated with deteriorated cGMP signalling in the myocardium (elevated phosphodiesterase-5 expression, lower cGMP-level and impaired PKG activity). Cardiomyocyte hypertrophy, fibrotic remodelling and DNA fragmentation were present in DM that was associated with impaired LV contractility (preload recruitable stroke work (PRSW): 49.5±3.3 vs. 83.0±5.5mmHg, P

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