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

  • Cardiovasc Diabetol. 2015 Oct 31;14:145. doi: 10.1186/s12933-015-0309-x.
Csaba Mátyás  1 ,  Balázs Tamás Németh  2 ,  Attila Oláh  3 ,  László Hidi  4 ,  Ede Birtalan  5 ,  Dalma Kellermayer  6 ,  Mihály Ruppert  7 ,  Sevil Korkmaz-Icöz  8 ,  Gábor Kökény  9 ,  Eszter Mária Horváth  10 ,  Gábor Szabó  11 ,  Béla Merkely  12 ,  Tamás Radovits  13  14
Affiliations
  • 1. Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. [email protected].
  • 2. Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. [email protected].
  • 3. Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. [email protected].
  • 4. Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. [email protected].
  • 5. Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. [email protected].
  • 6. Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. [email protected].
  • 7. Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. [email protected].
  • 8. Experimental Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, INF 326. OG 2, 69120, Heidelberg, Germany. [email protected].
  • 9. Institute of Pathophysiology, Semmelweis University, Nagyvárad tér 4., Budapest, 1089, Hungary. [email protected].
  • 10. Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Tűzoltó u. 37-47., Budapest, 1094, Hungary. [email protected].
  • 11. Experimental Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, INF 326. OG 2, 69120, Heidelberg, Germany. [email protected].
  • 12. Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. [email protected].
  • 13. Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary. [email protected].
  • 14. Experimental Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, INF 326. OG 2, 69120, Heidelberg, Germany. [email protected].
PMID: 26520063 DOI: 10.1186/s12933-015-0309-x
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.

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