LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease
LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease
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DOI：
10.1016/j.cardfail.2017.12.010
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发表时间：
2018-04-01
影响因子：
6
通讯作者：
Moradi, Hamid
中科院分区：
文献类型：
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作者：
Suematsu, Yasunori;Jing, Wanghui;Moradi, Hamid
背景：慢性肾脏疾病(CKD)与心肌肥大、纤维化和心血管死亡风险增加有关。LCZ696(萨舒比利/valsartan)是一种很有前途的药物，已显示出在治疗心力衰竭方面的巨大潜力。方法与结果：雄性SD大鼠行5/6肾切除手术后，随机分为3组：不治疗组(CKD)、缬沙坦30 mg/kg(Val)、LCZ696(LCZ)60 mg/kg。8周后，测量心血管参数，包括炎症、氧化应激、线粒体丰度/功能、肥大和纤维化的标志物。治疗后心重比、血清N末端B型利钠肽原和成纤维细胞生长因子23水平明显改善，肾功能改善。此外，LCZ还可改善主动脉纤维化、心肌肥大和纤维化，降低心脏氧化应激和炎症的标记物，并改善线粒体质量/功能指标。虽然Val也改善了其中的一些指标，但与单独应用Val相比，使用Lcz的治疗效果更好。结论：与单独使用Val相比，Lcz治疗能更有效地减轻CKD相关的心血管异常，包括心肌肥大、纤维化、炎症、氧化应激和线粒体耗竭/功能障碍。
Background: Chronic kidney disease (CKD) is associated with cardiac hypertrophy, fibrosis, and increased risk of cardiovascular mortality. LCZ696 (sacubitril/valsartan) is a promising agent that has shown significant potential in treatment of heart failure. We hypothesized that LCZ696 is more effective than valsartan alone in the treatment of cardiovascular abnormalities associated with experimental CKD.Methods and Results: Male Sprague-Dawley rats underwent 5/6 nephrectomy and were subsequently randomized to no treatment (CKD), 30 mg/kg valsartan (VAL), or 60 mg/kg LCZ696 (LCZ). After 8 weeks, cardiovascular parameters, including markers of inflammation, oxidative stress, mitochondrial abundance/function, hypertrophy, and fibrosis, were measured. Treatment with LCZ resulted in significant improvements in the heart-body weight ratio and serum concentrations of N-terminal pro-B-type natriuretic peptide and fibroblast growth factor 23 along with improvement of kidney function. In addition, LCZ ameliorated aortic fibrosis and cardiac hypertrophy and fibrosis, reduced markers of cardiac oxidative stress and inflammation, and improved indicators of mitochondrial mass/function. Although VAL also improved some of these indices, treatment with LCZ was more effective than VAL alone.Conclusions: CKD-associated cardiovascular abnormalities, including myocardial hypertrophy, fibrosis, inflammation, oxidative stress, and mitochondrial depletion/dysfunction, were more effectively attenuated by LCZ treatment than by VAL alone.