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Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.
Circulation ( IF 37.8 ) Pub Date : 2020-01-17 , DOI: 10.1161/circulationaha.119.042559
Katharina Schimmel 1 , Mira Jung 1 , Ariana Foinquinos 1 , Gorka San José 2, 3 , Javier Beaumont 2, 3 , Katharina Bock 1 , Lea Grote-Levi 1 , Ke Xiao 1 , Christian Bär 1 , Angelika Pfanne 1 , Annette Just 1 , Karina Zimmer 1 , Soeun Ngoy 4 , Begoña López 2, 3 , Susana Ravassa 2, 3 , Sabine Samolovac 1 , Heike Janssen-Peters 1 , Janet Remke 1 , Kristian Scherf 1, 5 , Seema Dangwal 1, 5 , Maria-Teresa Piccoli 1 , Felix Kleemiss 1 , Fabian Philipp Kreutzer 1 , Franziska Kenneweg 1 , Julia Leonardy 1 , Lisa Hobuß 1 , Laura Santer 1 , Quoc-Tuan Do 6 , Robert Geffers 7 , Jan Hinrich Braesen 8 , Jessica Schmitz 8 , Christina Brandenberger 9 , Dominik N Müller 10 , Nicola Wilck 10, 11 , Volkhard Kaever 12 , Heike Bähre 12 , Sandor Batkai 1 , Jan Fiedler 1 , Kevin M Alexander 5 , Bradley M Wertheim 13 , Sudeshna Fisch 4 , Ronglih Liao 4, 5 , Javier Diez 2, 3, 14 , Arantxa González 2, 3 , Thomas Thum 1, 15
Affiliation  

BACKGROUND Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure development, a leading cause of deaths worldwide. Clinically, no therapeutic strategy is available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, our aim was to develop novel antifibrotic therapeutics based on naturally derived substance library screens for the treatment of cardiac fibrosis. METHODS Antifibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts, subsequent validation, and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of human cardiac fibroblasts, modulation of apoptosis, and extracellular matrix expression. In vitro findings were confirmed in vivo with an angiotensin II-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt-sensitive rat model. To investigate the mechanism underlying the antifibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary human cardiac fibroblasts were analyzed by RNA deep sequencing. RESULTS High-throughput natural compound library screening identified 15 substances with antiproliferative effects in human cardiac fibroblasts. Using multiple in vitro fibrosis assays and stringent selection algorithms, we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective antifibrotic molecules both in vitro and in vivo, leading to improvement in diastolic function in 2 hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers or the morphology of kidney and liver, providing the first toxicological safety data. Using next-generation sequencing, we identified the conserved microRNA 671-5p and downstream the antifibrotic selenoprotein P1 as common effectors of the antifibrotic compounds. CONCLUSIONS We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.

中文翻译:

天然化合物文库筛选确定了用于治疗心脏纤维化和舒张功能障碍的新分子。

背景技术心肌纤维化是心脏重塑的标志,并且在功能上涉及心力衰竭的发展,而心力衰竭是世界范围内死亡的主要原因。临床上,尚无可特异性减弱心脏成纤维细胞(心脏纤维化的效应细胞)的适应不良反应的治疗策略。因此,我们的目的是开发基于天然物质库筛选的新型抗纤维化疗法,以治疗心脏纤维化。方法通过功能筛选人原代心脏成纤维细胞中的480种化学性质多样的天然化合物,随后的验证以及体外和体内机制研究,确定候选抗纤维化药物。分析了命中物中人心脏成纤维细胞增殖的剂量依赖性抑制,凋亡的调节,和细胞外基质表达。在预防和治疗方面以及在Dahl盐敏感性大鼠模型中,血管紧张素II介导的小鼠心脏纤维化鼠模型在体内均证实了体外发现。为了研究潜在的先导化合物抗纤维化的机制,通过RNA深度测序分析了人类心脏成纤维细胞中非编码RNAome的治疗依赖性变化。结果高通量天然化合物文库筛选鉴定出15种在人心脏成纤维细胞中具有抗增殖作用的物质。使用多种体外纤维化检测方法和严格的选择算法,我们确定了类固醇蟾蜍灵(来自蟾蜍毒液)和生物碱lycorine(来自芳科植物)在体内外均是有效的抗纤维化分子,导致2种高血压依赖性啮齿动物心脏纤维化模型中舒张功能的改善。有效剂量给药未改变血浆损伤标志物或肾脏和肝脏的形态,提供了第一份毒理学安全性数据。使用下一代测序,我们确定了保守的microRNA 671-5p和下游的抗纤维化硒蛋白P1是抗纤维化化合物的常见效应子。结论我们确定了bufalin和lycorine分子是在心脏纤维化和舒张功能障碍中治疗应用的候选药物。提供第一份毒理学安全性数据。使用下一代测序,我们确定了保守的microRNA 671-5p和下游的抗纤维化硒蛋白P1是抗纤维化化合物的常见效应子。结论我们确定了bufalin和lycorine分子是在心脏纤维化和舒张功能障碍中治疗应用的候选药物。提供第一份毒理学安全性数据。使用下一代测序,我们确定了保守的microRNA 671-5p和下游的抗纤维化硒蛋白P1是抗纤维化化合物的常见效应子。结论我们确定了bufalin和lycorine分子是在心脏纤维化和舒张功能障碍中治疗应用的候选药物。
更新日期:2020-01-17
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