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, A. Oláh, Eszter M. Horváth, G. Verès, Sven Pleger, Niels Grabe, B. Merkely, Matthias Karck, T. Radovits, G. 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

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Left Ventricular Hypertrophy
Pharmacology
Pressure
Oxidative Stress
Cyclic GMP
Apoptosis
Hypertrophy
Fibrosis
Recovery of Function
Ventricular Pressure
Constriction
Echocardiography
Soluble Guanylyl Cyclase
Myocardium
Collagen
Placebos
BAY 58-2667
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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Comparison of the reverse-remodeling effect of pharmacological soluble guanylate cyclase activation with pressure unloading in pathological myocardial left ventricular hypertrophy. / Ruppert, Mihály; Korkmaz-Icöz, Sevil; Li, Shiliang; Brlecic, Paige; Németh, Balázs Tamás; Oláh, A.; Horváth, Eszter M.; Verès, G.; Pleger, Sven; Grabe, Niels; Merkely, B.; Karck, Matthias; Radovits, T.; Szabó, G.

In: Frontiers in Physiology, Vol. 10, No. JAN, 1869, 01.01.2019.

Research output: Article

Ruppert, Mihály ; Korkmaz-Icöz, Sevil ; Li, Shiliang ; Brlecic, Paige ; Németh, Balázs Tamás ; Oláh, A. ; Horváth, Eszter M. ; Verès, G. ; Pleger, Sven ; Grabe, Niels ; Merkely, B. ; Karck, Matthias ; Radovits, T. ; Szabó, G. / Comparison of the reverse-remodeling effect of pharmacological soluble guanylate cyclase activation with pressure unloading in pathological myocardial left ventricular hypertrophy. In: Frontiers in Physiology. 2019 ; Vol. 10, No. JAN.
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T1 - Comparison of the reverse-remodeling effect of pharmacological soluble guanylate cyclase activation with pressure unloading in pathological myocardial left ventricular hypertrophy

AU - Ruppert, Mihály

AU - Korkmaz-Icöz, Sevil

AU - Li, Shiliang

AU - Brlecic, Paige

AU - Németh, Balázs Tamás

AU - Oláh, A.

AU - Horváth, Eszter M.

AU - Verès, G.

AU - Pleger, Sven

AU - Grabe, Niels

AU - Merkely, B.

AU - Karck, Matthias

AU - Radovits, T.

AU - Szabó, G.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - CGMP

KW - Cinaciguat

KW - Left ventricular hypertrophy

KW - Pressure unloading

KW - Reverse remodeling

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