title: The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus.
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 (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 < 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.
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. csaba.matyas@gmail.com.
authors.forename: Csaba
authors.initials: C
authors.lastname: Mátyás
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. nemethbl@gmail.com.
authors.forename: Balázs Tamás
authors.initials: BT
authors.lastname: Németh
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. o.attilio@gmail.com.
authors.forename: Attila
authors.initials: A
authors.lastname: Oláh
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. hidil88@gmail.com.
authors.forename: László
authors.initials: L
authors.lastname: Hidi
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. birtalanede@gmail.com.
authors.forename: Ede
authors.initials: E
authors.lastname: Birtalan
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. dalmakeller@gmail.com.
authors.forename: Dalma
authors.initials: D
authors.lastname: Kellermayer
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. ruppertm@gmail.hu.
authors.forename: Mihály
authors.initials: M
authors.lastname: Ruppert
authors.affiliation: Experimental Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, INF 326. OG 2, 69120, Heidelberg, Germany. korkmaz_sevil@hotmail.com.
authors.forename: Sevil
authors.initials: S
authors.lastname: Korkmaz-Icöz
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Nagyvárad tér 4., Budapest, 1089, Hungary. gabor.kokeny@gmail.com.
authors.forename: Gábor
authors.initials: G
authors.lastname: Kökény
authors.affiliation: Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Tűzoltó u. 37-47., Budapest, 1094, Hungary. heszterm@gmail.com.
authors.forename: Eszter Mária
authors.initials: EM
authors.lastname: Horváth
authors.affiliation: Experimental Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, INF 326. OG 2, 69120, Heidelberg, Germany. gabor.szabo@urz.uni-heidelberg.de.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. merkely.bela@gmail.com.
authors.forename: Béla
authors.initials: B
authors.lastname: Merkely
authors.affiliation: Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. radovitstamas@yahoo.com.|Experimental Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, INF 326. OG 2, 69120, Heidelberg, Germany. radovitstamas@yahoo.com.
authors.forename: Tamás
authors.initials: T
authors.lastname: Radovits
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies; D004195:Disease Models, Animal; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009206:Myocardium / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats
chemical_list: D001565:Benzoates; D009569:Nitric Oxide; C480588:BAY 58-2667; D006152:Cyclic GMP