Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy
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...
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Frontiers Media S.A.
2019-01-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2018.01869/full |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy Frontiers in Physiology left ventricular hypertrophy pressure unloading reverse remodeling cinaciguat cGMP |
author_facet |
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 |
author_sort |
Mihály Ruppert |
title |
Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy |
title_short |
Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy |
title_full |
Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy |
title_fullStr |
Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy |
title_full_unstemmed |
Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy |
title_sort |
comparison of the reverse-remodeling effect of pharmacological soluble guanylate cyclase activation with pressure unloading in pathological myocardial left ventricular hypertrophy |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2019-01-01 |
description |
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. |
topic |
left ventricular hypertrophy pressure unloading reverse remodeling cinaciguat cGMP |
url |
https://www.frontiersin.org/article/10.3389/fphys.2018.01869/full |
work_keys_str_mv |
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doaj-cf189accbc1641079b76ccfe12690df72020-11-25T00:46:27ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-01-01910.3389/fphys.2018.01869422864Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular HypertrophyMihály Ruppert0Mihály Ruppert1Sevil Korkmaz-Icöz2Shiliang Li3Paige Brlecic4Balázs Tamás Németh5Attila Oláh6Eszter M. Horváth7Gábor Veres8Sven Pleger9Niels Grabe10Niels Grabe11Béla Merkely12Matthias Karck13Tamás Radovits14Gábor Szabó15Experimental Research Laboratory, Heart and Vascular Center, Semmelweis University, Budapest, HungaryLaboratory of Experimental Cardiac Surgery, Department of Cardiac Surgery, Heidelberg University, Heidelberg, GermanyLaboratory of Experimental Cardiac Surgery, Department of Cardiac Surgery, Heidelberg University, Heidelberg, GermanyLaboratory of Experimental Cardiac Surgery, Department of Cardiac Surgery, Heidelberg University, Heidelberg, GermanyLaboratory of Experimental Cardiac Surgery, Department of Cardiac Surgery, Heidelberg University, Heidelberg, GermanyExperimental Research Laboratory, Heart and Vascular Center, Semmelweis University, Budapest, HungaryExperimental Research Laboratory, Heart and Vascular Center, Semmelweis University, Budapest, HungaryLaboratory of Oxidative Stress, Department of Physiology, Institute of Clinical Experimental Research, Semmelweis University, Budapest, HungaryLaboratory of Experimental Cardiac Surgery, Department of Cardiac Surgery, Heidelberg University, Heidelberg, GermanyLaboratory for Molecular and Translational Cardiology, Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, Heidelberg, GermanyResearch Group on Epidermal Systems Biology, Hamamatsu Tissue Imaging and Analysis Center, Bioquant, Heidelberg University, Heidelberg, GermanyNational Center for Tumor Diseases, Medical Oncology, Heidelberg University Hospital, Heidelberg University, Heidelberg, GermanyExperimental Research Laboratory, Heart and Vascular Center, Semmelweis University, Budapest, HungaryLaboratory of Experimental Cardiac Surgery, Department of Cardiac Surgery, Heidelberg University, Heidelberg, GermanyExperimental Research Laboratory, Heart and Vascular Center, Semmelweis University, Budapest, HungaryLaboratory of Experimental Cardiac Surgery, Department of Cardiac Surgery, Heidelberg University, Heidelberg, GermanyBackground: 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.https://www.frontiersin.org/article/10.3389/fphys.2018.01869/fullleft ventricular hypertrophypressure unloadingreverse remodelingcinaciguatcGMP |