TY  - JOUR
PB  - BioMed Central
CY  - London
TI  - The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/19721/
SN  - 1475-2840
IS  - 145
VL  - 14
ID  - heidok19721
AV  - public
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 (10 mg/kg/day) or with placebo orally for 8 weeks. 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 ± 5.5 mmHg, P < 0.05) and diastolic function (time constant of LV pressure decay (Tau): 17.3 ± 0.8 vs. 10.3 ± 0.3 ms, P &lt; 0.05). Cinaciguat treatment effectively prevented DM related molecular, histological alterations and significantly improved systolic (PRSW: 66.8 ± 3.6 mmHg) and diastolic (Tau: 14.9 ± 0.6 ms) function.   Conclusions: Cinaciguat prevented structural, molecular alterations and improved cardiac performance of the diabetic heart. Pharmacological activation of sGC might represent a new therapy approach for diabetic cardiomyopathy.  
Y1  - 2015///
SP  - 1
A1  - Mátyás, Csaba
A1  - Németh, Balázs Tamás
A1  - Oláh, Attila
A1  - Hidi, László
A1  - Birtalan, Ede
A1  - Kellermayer, Dalma
A1  - Ruppert, Mihály
A1  - Korkmaz-Icöz, Sevil
A1  - Kökény, Gábor
A1  - Horváth, Eszter Mária
A1  - Szabó, Gábor
A1  - Merkely, Béla
A1  - Radovits, Tamás
JF  - Cardiovascular diabetology
EP  - 13
ER  -