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Published on: March 24, 2023
A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy
Zhenya Wang1,2, Wei Shi1,2, Taibo Wu1,2
1Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, China.
Insights
Luteolin effectively treats cardiac hypertrophy and heart failure by targeting PPARγ degradation. This natural compound shows promise for heart conditions and metabolic disorders.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Pathological cardiac hypertrophy, often caused by pressure overload or metabolic issues, leads to heart failure.
- Current treatments lack specificity, highlighting the need for new therapeutic agents.
- Identifying novel drugs for cardiac hypertrophy and related metabolic disorders is crucial.
Purpose of the Study:
- To identify potential anti-hypertrophic drugs using high-throughput screening.
- To evaluate luteolin's efficacy and mechanism in cardiac hypertrophy and heart failure models.
- To explore luteolin's therapeutic potential for metabolic disorders associated with heart conditions.
Main Methods:
- Conducted a high-throughput screen of FDA-approved compounds using a luciferase reporter assay.
- Systematically assessed luteolin's effects on cardiac hypertrophy and heart failure in vitro and in vivo.
- Utilized transcriptome analysis to elucidate luteolin's molecular mechanisms and identified peroxisome proliferator activated receptor γ (PPARγ) as a direct target.
Main Results:
- Luteolin was identified as a potent inhibitor of cardiomyocyte hypertrophy among 2,570 screened compounds.
- Luteolin demonstrated dose-dependent inhibition of phenylephrine-induced hypertrophy and provided cardioprotection.
- In vivo studies showed luteolin ameliorated cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice by targeting PPARγ degradation.
Conclusions:
- Luteolin is a promising therapeutic agent for pathological cardiac hypertrophy and heart failure.
- Luteolin directly targets the ubiquitin-proteasomal degradation of PPARγ, restoring metabolic homeostasis.
- These findings support luteolin's potential for treating heart failure and associated metabolic disorders.
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.
