Rüdebusch Julia, Benkner Alexander, Nath Neetika, Fleuch Lina, Kaderali Lars, Grube Karina, Klingel Karin, Eckstein Gertrud, Meitinger Thomas, Fielitz Jens, Felix Stephan B
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
DZHK (German Centre for Cardiovascular Research, partner site Greifswald), Greifswald, Germany.
Br J Pharmacol. 2022 Jun;179(11):2430-2442. doi: 10.1111/bph.15333. Epub 2020 Dec 29.
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.
心力衰竭与一氧化氮-可溶性鸟苷酸环化酶（sGC）-环磷酸鸟苷（cGMP）信号通路受损有关，增强该信号通路被认为对心力衰竭治疗有益。我们推测，sGC激动剂利奥西呱刺激sGC可预防慢性压力超负荷引起的病理性心脏重塑和心力衰竭。
对C57BL/6N小鼠进行主动脉缩窄或假手术。在主动脉缩窄3周建立心力衰竭模型后，动物再接受利奥西呱或其溶媒治疗5周。每周通过超声心动图评估心脏功能。术后8周，进行组织学分析以评估心脏重塑，并通过RNA测序分析左心室（LV）的转录组。细胞培养实验用于机制研究。
主动脉缩窄导致左心室射血分数持续下降，左心室质量在第3周前增加。利奥西呱治疗5周可改善左心室射血分数，降低左心室质量与体重之比（LVM/BW）、心肌纤维化和心肌细胞横截面积。RNA测序显示，利奥西呱可降低心肌应激和重塑基因（如Nppa、Nppb、Myh7和胶原蛋白）的表达，并减弱与心肌肥大和心力衰竭相关的生物通路的激活。利奥西呱可逆转培养的心肌细胞和成纤维细胞中的病理性应激反应。
刺激sGC可逆转主动脉缩窄诱导的心力衰竭和心脏重塑，这与心肌基因表达改善有关。
本文是关于细胞生长和存活中cGMP信号传导的主题系列文章的一部分。要查看本部分的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc。
