The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction
in a rat model of type-1 diabetes mellitus
#MMPMID26520063
Mátyás C
; Németh BT
; Oláh A
; Hidi L
; Birtalan E
; Kellermayer D
; Ruppert M
; Korkmaz-Icöz S
; Kökény G
; Horváth EM
; Szabó G
; Merkely B
; Radovits T
Cardiovasc Diabetol
2015[Oct]; 14
(?): 145
PMID26520063
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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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