Stimulation of soluble guanylyl cyclase (sGC) by riociguat attenuates heart failure and pathological cardiac remodelling
| العنوان: | Stimulation of soluble guanylyl cyclase (sGC) by riociguat attenuates heart failure and pathological cardiac remodelling |
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| المؤلفون: | Karin Klingel, Jens Fielitz, Thomas Meitinger, Karina Grube, Gertrud Eckstein, Stephan B. Felix, Julia Rüdebusch, Lina Fleuch, Alexander Benkner, Lars Kaderali, Neetika Nath |
| المصدر: | Br. J. Pharmacol., DOI: 10.1111/bph.15333 (2020) |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Cardiac function curve, medicine.medical_specialty, Cgmp Signalling, Heart Failure, Riociguat, Rna Sequencing, Soluble Gc, Tac, Mice, 03 medical and health sciences, Soluble Guanylyl Cyclase, 0302 clinical medicine, Internal medicine, medicine, Animals, Myocyte, Cyclic GMP, Pharmacology, Pressure overload, Ejection fraction, Ventricular Remodeling, business.industry, medicine.disease, Mice, Inbred C57BL, Pyrimidines, 030104 developmental biology, Heart failure, cardiovascular system, Cardiology, Pyrazoles, Myocardial fibrosis, business, Soluble guanylyl cyclase, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | Heart failure is associated with an impaired NO-soluble guanylyl cyclase (sGC)-cGMP pathway and its augmentation is thought to be beneficial for its therapy. We hypothesized that stimulation of sGC by the sGC stimulator riociguat prevents pathological cardiac remodelling and heart failure in response to chronic pressure overload.Transverse aortic constriction or sham surgery was performed in C57BL/6N mice. After 3 weeks of transverse aortic constriction when heart failure was established, animals receive either riociguat or its vehicle for 5 additional weeks. Cardiac function was evaluated weekly by echocardiography. Eight weeks after surgery, histological analyses were performed to evaluate remodelling and the transcriptome of the left ventricles (LVs) was analysed by RNA sequencing. Cell culture experiments were used for mechanistically studies.Transverse aortic constriction resulted in a continuous decrease of LV ejection fraction and an increase in LV mass until week 3. Five weeks of riociguat treatment resulted in an improved LV ejection fraction and a decrease in the ratio of left ventricular mass to total body weight (LVM/BW), myocardial fibrosis and myocyte cross-sectional area. RNA sequencing revealed that riociguat reduced the expression of myocardial stress and remodelling genes (e.g. Nppa, Nppb, Myh7 and collagen) and attenuated the activation of biological pathways associated with cardiac hypertrophy and heart failure. Riociguat reversed pathological stress response in cultivated myocytes and fibroblasts.Stimulation of the sGC reverses transverse aortic constriction-induced heart failure and remodelling, which is associated with improved myocardial gene expression.This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc. |
| وصف الملف: | application/pdf |
| تدمد: | 1476-5381 0007-1188 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e3dc01972edbe794fa689334cfe2f5bf https://doi.org/10.1111/bph.15333 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e3dc01972edbe794fa689334cfe2f5bf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765381 00071188 |
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