BackgroundPathological cardiac hypertrophy is commonly resulted from sustained pressure overload and/or metabolic disorder and eventually leads to heart failure, lacking specific drugs in clinic. Here, we aimed to identify promising anti-hypertrophic drug(s) for heart failure and related metabolic disorders by using a luciferase reporter-based high-throughput screening.MethodsA screen of the FDA-approved compounds based on luciferase reporter was performed, with identified luteolin as a promising anti-hypertrophic drug. We systematically examined the therapeutic efficacy of luteolin on cardiac hypertrophy and heart failure in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin.ResultsAmong 2,570 compounds in the library, luteolin emerged as the most robust candidate against cardiomyocyte hypertrophy. Luteolin dose-dependently blocked phenylephrine-induced cardiomyocyte hypertrophy and showed extensive cardioprotective roles in cardiomyocytes as evidenced by transcriptomics. More importantly, gastric administration of luteolin effectively ameliorated pathological cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice. Cross analysis of large-scale transcriptomics and drug-target interacting investigations indicated that peroxisome proliferator activated receptor γ (PPARγ) was the direct target of luteolin in the setting of pathological cardiac hypertrophy and metabolic disorders. Luteolin can directly interact with PPARγ to inhibit its ubiquitination and subsequent proteasomal degradation. Furthermore, PPARγ inhibitor and PPARγ knockdown both prevented the protective effect of luteolin against phenylephrine-induced cardiomyocyte hypertrophy in vitro.ConclusionOur data clearly supported that luteolin is a promising therapeutic compound for pathological cardiac hypertrophy and heart failure by directly targeting ubiquitin-proteasomal degradation of PPARγ and the related metabolic homeostasis.

中文翻译：

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高通量药物筛选将木犀草素确定为病理性心脏肥大和心力衰竭的治疗候选药物

研究背景病理性心肌肥厚多由持续性压力超负荷和/或代谢紊乱引起，最终导致心力衰竭，临床上缺乏特效药。在这里，我们的目的是通过使用基于荧光素酶报告基因的高通量筛选来鉴定用于心力衰竭和相关代谢紊乱的有前途的抗肥大药物。木犀草素作为一种有前途的抗肥大药物。我们系统地检查了木犀草素对心脏肥大和心力衰竭的治疗效果体外和体内楷模。进行转录组检查以探究木犀草素的分子机制。结果在库中的 2,570 种化合物中，木犀草素成为抗心肌细胞肥大的最有力候选者。木犀草素以剂量依赖性方式阻断去氧肾上腺素诱导的心肌细胞肥大，并在心肌细胞中显示出广泛的心脏保护作用，转录组学证明了这一点。更重要的是，木犀草素的胃给药有效改善了小鼠的病理性心脏肥大、纤维化、代谢紊乱和心力衰竭。大规模转录组学和药物靶标相互作用研究的交叉分析表明，过氧化物酶体增殖物激活受体 γ (PPARγ) 是木犀草素在病理性心脏肥大和代谢紊乱中的直接靶标。木犀草素可以直接与 PPARγ 相互作用以抑制其泛素化和随后的蛋白酶体降解。此外，PPARγ 抑制剂和 PPARγ 敲低都阻止了木犀草素对去氧肾上腺素诱导的心肌细胞肥大的保护作用体外.Conclusion 我们的数据清楚地支持了木犀草素是一种有前景的治疗病理性心脏肥大和心力衰竭的化合物，它直接靶向 PPARγ 的泛素-蛋白酶体降解和相关的代谢稳态。