Wang Zhenya, Shi Wei, Wu Taibo, Peng Tian, Wang Xiaoming, Liu Shuaiyang, Yang Zifeng, Wang Jia, Li Peng-Long, Tian Ruifeng, Hong Ying, Yang Hailong, Bai Lan, Hu Yufeng, Cheng Xu, Li Hongliang, Zhang Xiao-Jing, She Zhi-Gang
Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China.
Institute of Model Animal, Wuhan University, Wuhan, China.
Front Cardiovasc Med. 2023 Mar 14;10:1130635. doi: 10.3389/fcvm.2023.1130635. eCollection 2023.
Pathological 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.
A 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 and models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin.
Among 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 .
Our 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.
病理性心脏肥大通常由持续的压力过载和/或代谢紊乱引起，最终导致心力衰竭，临床上缺乏特效药物。在此，我们旨在通过基于荧光素酶报告基因的高通量筛选，鉴定出有前景的用于治疗心力衰竭及相关代谢紊乱的抗肥大药物。
基于荧光素酶报告基因对美国食品药品监督管理局（FDA）批准的化合物进行筛选，确定木犀草素为一种有前景的抗肥大药物。我们系统地研究了木犀草素对心脏肥大和心力衰竭模型的治疗效果。进行转录组分析以探究木犀草素的分子机制。
在文库中的2570种化合物中，木犀草素成为对抗心肌细胞肥大最有效的候选药物。木犀草素剂量依赖性地阻断苯肾上腺素诱导的心肌细胞肥大，并如转录组学所示，在心肌细胞中发挥广泛的心脏保护作用。更重要的是，经胃给予木犀草素可有效改善小鼠的病理性心脏肥大、纤维化、代谢紊乱和心力衰竭。大规模转录组学与药物靶点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情况下的直接靶点。木犀草素可直接与PPARγ相互作用，抑制其泛素化及随后的蛋白酶体降解。此外，PPARγ抑制剂和PPARγ基因敲低均阻止了木犀草素对苯肾上腺素诱导的心肌细胞肥大的保护作用。
我们的数据明确支持，木犀草素通过直接靶向PPARγ的泛素-蛋白酶体降解及相关代谢稳态，是治疗病理性心脏肥大和心力衰竭的一种有前景的治疗化合物。
