Abstract
BackgroundDiabetes 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.MethodsType-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.ResultsDM 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.ConclusionsCinaciguat 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0309-x) contains supplementary material, which is available to authorized users.
Highlights
Diabetes mellitus (DM) leads to the development of diabetic cardiomyopathy, which is associated with altered nitric oxide (NO)—soluble guanylate cyclase—cyclic guanosine monophosphate signalling
Effects of cinaciguat on plasma and myocardial cyclic guanosine monophosphate (cGMP) levels in DM Cinaciguat treatment had no effect on plasma cGMP levels in control animals (Fig. 1a), it resulted in a pronounced increase of plasma cGMP in DM (Fig. 1a)
We found that chronic application of cinaciguat did not affect blood glucose levels, it effectively raised cGMP levels and restored cGMP-protein kinase G (PKG) signalling in the myocardium
Summary
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. Diabetes mellitus (DM) is associated with cardiovascular complications, such as myocardial infarction, chronic heart failure or vascular diseases. Under physiological conditions, nitric oxide (NO) is produced by the endothelial nitric oxide synthase (eNOS) in endothelial cells and diffuses into target cells, such as vascular smooth muscle cells or cardiomyocytes. It activates its intracellular receptor, the soluble guanylate cyclase enzyme (sGC) which results in the rapid formation of the second messenger cyclic guanosine monophosphate (cGMP). Drugs that are able to activate the NO-insensitive form of sGC reactivating it might have cardioprotective effects in various pathological conditions through the enhancement of the impaired cGMP-signalling. Recent studies described its beneficial effects in experimental myocardial infarction [18], myocardial ischemia/reperfusion injury [19, 20], endothelial dysfunction induced by nitro-oxidative stress [21], vascular neointima formation [22] or in prevention of cardiomyocyte hypertrophy [23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
