Frontiers in Physiology (Jan 2019)

Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy

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

DOI
https://doi.org/10.3389/fphys.2018.01869
Journal volume & issue
Vol. 9

Abstract

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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.

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