Ruppert Mihály, Korkmaz-Icöz Sevil, Li Shiliang, Brlecic Paige, Németh Balázs Tamás, Oláh Attila, Horváth Eszter M, Veres Gábor, Pleger Sven, Grabe Niels, Merkely Béla, Karck Matthias, Radovits Tamás, Szabó Gábor
Experimental Research Laboratory, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
Laboratory of Experimental Cardiac Surgery, Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany.
Front Physiol. 2019 Jan 8;9:1869. doi: 10.3389/fphys.2018.01869. eCollection 2018.
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. 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. 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. Our results indicate that both cinaciguat treatment and pressure unloading evoked anti-remodeling effects and improved LV function, however in a differing manners.
压力卸载可诱导左心室心肌肥厚（LVH）消退。最近的研究结果表明，可溶性鸟苷酸环化酶（sGC）-环磷酸鸟苷（cGMP）途径的药理学激活也可能在心肌中发挥逆向重塑作用。因此，我们旨在研究sGC激活剂西那吉酯在LVH大鼠模型中的作用，并将其与“金标准”压力卸载疗法进行比较。进行腹主动脉缩窄6周或12周。假手术动物作为对照。在第6周后通过去除主动脉缩窄诱导压力卸载。从第7周开始至第12周，分别用10mg/kg/天的西那吉酯或安慰剂口服治疗动物。通过左心室压力-容积分析和超声心动图评估心脏功能和形态。此外，还分析了心肌肥厚、纤维化、硝基氧化应激、细胞凋亡和cGMP信号传导的关键标志物。压力卸载有效地逆转了LVH，减少了胶原蛋白积累，并提供了抗氧化应激和细胞凋亡的保护作用。LVH的消退还与心脏功能的完全恢复相关。相比之下，在持续压力过载的情况下，西那吉酯对sGC酶的慢性激活仅轻微影响预先建立的肥厚。然而，它导致PKG活性增加，并对间质纤维化、硝基氧化应激和细胞凋亡产生显著影响。病理结构改变的改善防止了LV收缩功能（收缩力和射血分数）的恶化，并改善了心肌僵硬度。我们的结果表明，西那吉酯治疗和压力卸载均引发了抗重塑作用并改善了LV功能，但方式不同。
