Lcz696 Alleviates Myocardial Fibrosis After Myocardial Infarction Through the sFRP-1/Wnt/β-Catenin Signaling Pathway.
Lcz696 Alleviates Myocardial Fibrosis After Myocardial Infarction Through the sFRP-1/Wnt/β-Catenin Signaling Pathway.
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LcZ696通过SFRp-1/Wnt/β-Catenin信号通路减轻心肌梗死后心肌纤维化
DOI：
10.3389/fphar.2021.724147
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发表时间：
2021
影响因子：
5.6
通讯作者：
Bu P
中科院分区：
文献类型：
--
作者：
Liu J;Zheng X;Zhang C;Zhang C;Bu P
背景资料：Lcz 696（ARNI，血管紧张素受体-脑啡肽酶抑制剂;沙库巴曲/缬沙坦）显示出对心肌梗死（MI）后纤维化的抑制作用。然而，对潜在的信号传导机制知之甚少。Wnt/β-catenin信号通路在心肌梗死后被激活，参与心肌纤维化过程。在此，我们旨在评估ARNI缓解MI后心肌纤维化的疗效，并假设ARNI通过抑制Wnt/β-catenin信号通路和过表达sFRP-1（Wnt/β-catenin信号通路的抑制剂）来减轻心肌纤维化。研究方法：在MI后1周随机化的小鼠口服给予lcz 696（60 mg/kg，n = 21）、缬沙坦（30 mg/kg，n = 19）或玉米油（n = 13）持续4周，而假手术组接受媒介物（玉米油，n = 19）。测定心功能和心肌纤维化程度。采用Western blotting和实时荧光定量PCR检测Wnt/β-catenin通路相关蛋白的表达。用血管紧张素II（Ang II）刺激原代心肌成纤维细胞，并与lcz 696和sFRP-1抑制剂way 316606共同培养，检测Wnt/β-catenin通路蛋白的表达。结果如下：lcz 696和缬沙坦均能减轻心肌纤维化，改善心功能，但lcz 696的疗效上级缬沙坦。此外，药物治疗后小鼠β-连环蛋白表达受到抑制，sFRP-1过表达，lcz 696可以显着改善这种情况。此外，lcz 696抑制AngII刺激的心肌成纤维细胞中的β-catenin表达，并且在sFRP-1抑制后β-catenin表达增加。结论：ARNI通过抑制Wnt/β-catenin信号通路减轻心肌纤维化和心肌重塑。此外，ARNI可导致sFRP-1的过表达，sFRP-1是Wnt/β-连环蛋白信号通路的抑制剂。这些结果提示ARNI改善心肌纤维化和防止心肌重塑是一个新的治疗靶点。
Background: Lcz696 (ARNI, angiotensin receptor–neprilysin inhibitor; sacubitril/valsartan) shows an inhibitory effect on fibrosis after myocardial infarction (MI). However, the underlying signaling mechanisms are poorly understood. The Wnt/β-catenin signaling pathway is activated after MI and participates in the process of myocardial fibrosis. Here, we aimed to assess the efficacy of ARNI for alleviating myocardial fibrosis after MI and hypothesized that ARNI alleviates myocardial fibrosis by inhibiting the Wnt/β-catenin signaling pathway and overexpressing sFRP-1, an inhibitor of the Wnt/β-catenin signaling pathway. Methods: Mice randomized at 1 week post-MI were administered lcz696 (60 mg/kg, n = 21), valsartan (30 mg/kg, n = 19), or corn oil (n = 13) orally for 4 weeks, while the sham-operated group received vehicle (corn oil, n = 19). Cardiac function and extent of myocardial fibrosis were measured. Western blotting and quantitative real-time polymerase chain reaction were used to detect the expression of Wnt/β-catenin pathway-related proteins. Furthermore, primary myocardial fibroblasts were stimulated with angiotensin II (Ang II) and cultured with lcz696 and the sFRP-1 inhibitor way316606 to detect the expression of Wnt/β-catenin pathway proteins. Results: Both lcz696 and valsartan alleviated myocardial fibrosis and improved cardiac function, but lcz696 had superior efficiency compared to valsartan. Furthermore, β-catenin expression was inhibited and sFRP-1 was overexpressed after drug treatment, which could be significantly improved by lcz696 in mice. In addition, lcz696 inhibited β-catenin expression in AngII-stimulated myocardial fibroblasts, and β-catenin expression increased after the inhibition of sFRP-1. Conclusion: ARNI alleviated cardiac fibrosis and cardiac remodeling by inhibiting the Wnt/β-catenin signaling pathway. In addition, ARNI can lead to overexpression of sFRP-1, which is an inhibitor of the Wnt/β-catenin signaling pathway. These results indicate a new therapeutic target of ARNI to improve myocardial fibrosis and prevent myocardial remodeling.
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