SCIENTIFIC JOURNAL of the Hungarian Society of Cardiology

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

█ Original article

DOI: 10.26430/CHUNGARICA.2017.47.1.34

Mátyás Csaba1*, Barta Bálint András1*, Németh Balázs Tamás1, Oláh Attila1, Hidi László1, Birtalan Ede1, Kellermayer Dalma1, Ruppert Mihály1, Korkmaz-Icöz Sevil2, Kökény Gábor3, Horváth Eszter Mária4, Szabó Gábor2, Merkely Béla1, Radovits Tamás1
1Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika, Kísérleti Kutató Laboratórium, Budapest
2Ruprecht-Karls Egyetem, Szívsebészeti Klinika, Kísérleti Kutató Laboratórium, Heidelberg, Németország
3Semmelweis Egyetem, Kórélettani Intézet, Budapest
4Semmelweis Egyetem, Élettani Intézet, Budapest
*A szerzők a munkához egyenlő mértékben járultak hozzá.


Introduction: 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) signaling. Cardio-protective 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 remodeling and DNA fragmentation were present in DM that was associated with impaired LV contractility and diastolic function. Cinaciguat treatment effectively prevented DM related molecular, histological alterations and significantly improved systolic and diastolic 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.


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