A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure
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 d...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-03-01
|
| Series: | Frontiers in Cardiovascular Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1130635/full |
| _version_ | 1797871230997495808 |
|---|---|
| author | Zhenya Wang Zhenya Wang Wei Shi Wei Shi Taibo Wu Taibo Wu Tian Peng Tian Peng Xiaoming Wang Xiaoming Wang Shuaiyang Liu Shuaiyang Liu Zifeng Yang Zifeng Yang Jia Wang Jia Wang Peng-Long Li Peng-Long Li Ruifeng Tian Ruifeng Tian Ying Hong Hailong Yang Lan Bai Yufeng Hu Xu Cheng Hongliang Li Hongliang Li Hongliang Li Hongliang Li Xiao-Jing Zhang Xiao-Jing Zhang Zhi-Gang She Zhi-Gang She |
| author_facet | Zhenya Wang Zhenya Wang Wei Shi Wei Shi Taibo Wu Taibo Wu Tian Peng Tian Peng Xiaoming Wang Xiaoming Wang Shuaiyang Liu Shuaiyang Liu Zifeng Yang Zifeng Yang Jia Wang Jia Wang Peng-Long Li Peng-Long Li Ruifeng Tian Ruifeng Tian Ying Hong Hailong Yang Lan Bai Yufeng Hu Xu Cheng Hongliang Li Hongliang Li Hongliang Li Hongliang Li Xiao-Jing Zhang Xiao-Jing Zhang Zhi-Gang She Zhi-Gang She |
| author_sort | Zhenya Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T00:40:54Z |
| format | Article |
| id | doaj.art-9dc49f7980384b90a95bcbc593006ced |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-10T00:40:54Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-9dc49f7980384b90a95bcbc593006ced2023-03-14T06:00:57ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-03-011010.3389/fcvm.2023.11306351130635A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failureZhenya Wang0Zhenya Wang1Wei Shi2Wei Shi3Taibo Wu4Taibo Wu5Tian Peng6Tian Peng7Xiaoming Wang8Xiaoming Wang9Shuaiyang Liu10Shuaiyang Liu11Zifeng Yang12Zifeng Yang13Jia Wang14Jia Wang15Peng-Long Li16Peng-Long Li17Ruifeng Tian18Ruifeng Tian19Ying Hong20Hailong Yang21Lan Bai22Yufeng Hu23Xu Cheng24Hongliang Li25Hongliang Li26Hongliang Li27Hongliang Li28Xiao-Jing Zhang29Xiao-Jing Zhang30Zhi-Gang She31Zhi-Gang She32Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaGannan Innovation and Translational Medicine Research Institute, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, ChinaGannan Innovation and Translational Medicine Research Institute, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, ChinaGannan Innovation and Translational Medicine Research Institute, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, ChinaGannan Innovation and Translational Medicine Research Institute, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaGannan Innovation and Translational Medicine Research Institute, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, ChinaMedical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan, ChinaInstitute of Model Animal, Wuhan University, Wuhan, ChinaBackgroundPathological 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.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1130635/fullluteolincardiac hypertrophyheart failureperoxisome proliferator activated receptor γfatty acid metabolismglucose metabolism |
| spellingShingle | Zhenya Wang Zhenya Wang Wei Shi Wei Shi Taibo Wu Taibo Wu Tian Peng Tian Peng Xiaoming Wang Xiaoming Wang Shuaiyang Liu Shuaiyang Liu Zifeng Yang Zifeng Yang Jia Wang Jia Wang Peng-Long Li Peng-Long Li Ruifeng Tian Ruifeng Tian Ying Hong Hailong Yang Lan Bai Yufeng Hu Xu Cheng Hongliang Li Hongliang Li Hongliang Li Hongliang Li Xiao-Jing Zhang Xiao-Jing Zhang Zhi-Gang She Zhi-Gang She A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure Frontiers in Cardiovascular Medicine luteolin cardiac hypertrophy heart failure peroxisome proliferator activated receptor γ fatty acid metabolism glucose metabolism |
| title | A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure |
| title_full | A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure |
| title_fullStr | A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure |
| title_full_unstemmed | A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure |
| title_short | A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure |
| title_sort | high throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure |
| topic | luteolin cardiac hypertrophy heart failure peroxisome proliferator activated receptor γ fatty acid metabolism glucose metabolism |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1130635/full |
| work_keys_str_mv | AT zhenyawang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zhenyawang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT weishi ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT weishi ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT taibowu ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT taibowu ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT tianpeng ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT tianpeng ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xiaomingwang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xiaomingwang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT shuaiyangliu ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT shuaiyangliu ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zifengyang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zifengyang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT jiawang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT jiawang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT penglongli ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT penglongli ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT ruifengtian ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT ruifengtian ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT yinghong ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hailongyang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT lanbai ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT yufenghu ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xucheng ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hongliangli ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hongliangli ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hongliangli ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hongliangli ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xiaojingzhang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xiaojingzhang ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zhigangshe ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zhigangshe ahighthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zhenyawang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zhenyawang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT weishi highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT weishi highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT taibowu highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT taibowu highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT tianpeng highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT tianpeng highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xiaomingwang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xiaomingwang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT shuaiyangliu highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT shuaiyangliu highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zifengyang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zifengyang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT jiawang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT jiawang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT penglongli highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT penglongli highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT ruifengtian highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT ruifengtian highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT yinghong highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hailongyang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT lanbai highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT yufenghu highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xucheng highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hongliangli highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hongliangli highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hongliangli highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT hongliangli highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xiaojingzhang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT xiaojingzhang highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zhigangshe highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure AT zhigangshe highthroughputdrugscreeningidentifiesluteolinasatherapeuticcandidateforpathologicalcardiachypertrophyandheartfailure |