A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure

Zhenya Wang; Wei Shi; Taibo Wu; Tian Peng; Xiaoming Wang; Shuaiyang Liu; Zifeng Yang; Jia Wang; Peng-Long Li; Ruifeng Tian; Ying Hong; Hailong Yang; Lan Bai; Yufeng Hu; Xu Cheng; Hongliang Li; Xiao-Jing Zhang; Zhi-Gang She

doi:10.3389/fcvm.2023.1130635

A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure

Front Cardiovasc Med. 2023 Mar 14:10:1130635. doi: 10.3389/fcvm.2023.1130635. eCollection 2023.

Authors

Zhenya Wang^{1

2}, Wei Shi^{1

2}, Taibo Wu^{1

2}, Tian Peng^{1

2}, Xiaoming Wang^{1

2}, Shuaiyang Liu^{1

2}, Zifeng Yang^{1

2}, Jia Wang^{1

2}, Peng-Long Li^{1

2}, Ruifeng Tian^{1

2}, Ying Hong², Hailong Yang³, Lan Bai³, Yufeng Hu³, Xu Cheng³, Hongliang Li^{1

2

3

4}, Xiao-Jing Zhang^{1

2}, Zhi-Gang She^{1

2}

Affiliations

¹ Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China.
² Institute of Model Animal, Wuhan University, Wuhan, China.
³ Gannan Innovation and Translational Medicine Research Institute, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China.
⁴ Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.

Abstract

Background: 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.

Methods: 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 in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin.

Results: 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 in vitro.

Conclusion: 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.

Keywords: cardiac hypertrophy; fatty acid metabolism; glucose metabolism; heart failure; luteolin; peroxisome proliferator activated receptor γ.

Grants and funding

This work was supported by grants from the National Science Foundation of China (81970364, 82270390, 82170595 and 81970070), the Hubei Province Innovation Platform Construction Project (20204201117303072238), and the Hubei Provincial Engineering Research Center of Comprehensive Care for Heart-Brain Diseases.