Comparison of the reverse-remodeling effect of pharmacological soluble guanylate cyclase activation with pressure unloading in pathological myocardial left ventricular hypertrophy

Mihály Ruppert, Sevil Korkmaz-Icöz, Shiliang Li, Paige Brlecic, Balázs Tamás Németh, Attila Oláh, Eszter M. Horváth, Gábor Veres, Sven Pleger, Niels Grabe, Béla Merkely, Matthias Karck, Tamás Radovits, Gábor Szabó

Research output: Article

1 Citation (Scopus)

Abstract

Background: Pressure unloading induces the regression of left ventricular myocardial hypertrophy (LVH). Recent findings indicate that pharmacological activation of the soluble guanylate cyclase (sGC) -cyclic guanosine monophosphate (cGMP) pathway may also exert reverse-remodeling properties in the myocardium. Therefore, we aimed to investigate the effects of the sGC activator cinaciguat in a rat model of LVH and compare it to the "gold standard" pressure unloading therapy. Methods: Abdominal aortic banding was performed for 6 or 12 weeks. Sham operated animals served as controls. Pressure unloading was induced by removing the aortic constriction after week 6. The animals were treated from week 7 to 12, with 10 mg/kg/day cinaciguat or with placebo p.o., respectively. Cardiac function and morphology were assessed by left ventricular pressure-volume analysis and echocardiography. Additionally, key markers of myocardial hypertrophy, fibrosis, nitro-oxidative stress, apoptosis and cGMP signaling were analyzed. Results: Pressure unloading effectively reversed LVH, decreased collagen accumulation and provided protection against oxidative stress and apoptosis. Regression of LVH was also associated with a full recovery of cardiac function. In contrast, chronic activation of the sGC enzyme by cinaciguat at sustained pressure overload only slightly influenced pre-established hypertrophy. However, it led to increased PKG activity and had a significant impact on interstitial fibrosis, nitro-oxidative stress and apoptosis. Amelioration of the pathological structural alterations prevented the deterioration of LV systolic function (contractility and ejection fraction) and improved myocardial stiffness. Conclusion: Our results indicate that both cinaciguat treatment and pressure unloading evoked anti-remodeling effects and improved LV function, however in a differing manners.

Original languageEnglish
Article number1869
JournalFrontiers in Physiology
Volume10
Issue numberJAN
DOIs
Publication statusPublished - jan. 1 2019

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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