دورية أكاديمية
أعرض في EDS

Astragaloside IV derivative HHQ16 ameliorates infarction-induced hypertrophy and heart failure through degradation of lncRNA4012/9456.

التفاصيل البيبلوغرافية
العنوان: Astragaloside IV derivative HHQ16 ameliorates infarction-induced hypertrophy and heart failure through degradation of lncRNA4012/9456.
المؤلفون: Wan J; School of Pharmacy, Second Military Medical University, Shanghai, PR China., Zhang Z; School of Pharmacy, Second Military Medical University, Shanghai, PR China., Wu C; School of Pharmacy, Second Military Medical University, Shanghai, PR China., Tian S; School of Pharmacy, Second Military Medical University, Shanghai, PR China., Zang Y; School of Pharmacy, Second Military Medical University, Shanghai, PR China., Jin G; School of Pharmacy, Second Military Medical University, Shanghai, PR China., Sun Q; China Institute of Pharmaceutical Industry, Shanghai, PR China., Wang P; Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, PR China., Luan X; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China., Yang Y; China Regional Research Centre, International Centre of Genetic Engineering & Biotechnology, Taizhou, PR China., Zhan X; China Regional Research Centre, International Centre of Genetic Engineering & Biotechnology, Taizhou, PR China.; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, PR China., Ye LL; Center for Phenomics of Traditional Chinese Medicine, Hospital of Traditional Chinese Medicine Affiliated to Southwest Medical University, Southwest Medical University, Luzhou, PR China., Duan DD; Center for Phenomics of Traditional Chinese Medicine, Hospital of Traditional Chinese Medicine Affiliated to Southwest Medical University, Southwest Medical University, Luzhou, PR China. dduan@swmu.edu.cn.; Key Laboratory of Autoimmune Diseases and Precision Medicine, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, PR China. dduan@swmu.edu.cn., Liu X; School of Pharmacy, Second Military Medical University, Shanghai, PR China. lxflying@aliyun.com., Zhang W; School of Pharmacy, Second Military Medical University, Shanghai, PR China. wdzhangy@hotmail.com.; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China. wdzhangy@hotmail.com.
المصدر: Signal transduction and targeted therapy [Signal Transduct Target Ther] 2023 Oct 19; Vol. 8 (1), pp. 414. Date of Electronic Publication: 2023 Oct 19.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101676423 Publication Model: Electronic Cited Medium: Internet ISSN: 2059-3635 (Electronic) Linking ISSN: 20593635 NLM ISO Abbreviation: Signal Transduct Target Ther Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Publishing Group, [2016]-
مواضيع طبية MeSH: Heart Failure*/drug therapy , Heart Failure*/genetics , Myocardial Infarction*/drug therapy , Myocardial Infarction*/genetics , Myocardial Infarction*/metabolism, Humans ; Mice ; Animals ; Myocytes, Cardiac/metabolism ; Cardiomegaly/drug therapy ; Cardiomegaly/genetics ; Cardiomegaly/metabolism
مستخلص: Reversing ventricular remodeling represents a promising treatment for the post-myocardial infarction (MI) heart failure (HF). Here, we report a novel small molecule HHQ16, an optimized derivative of astragaloside IV, which effectively reversed infarction-induced myocardial remodeling and improved cardiac function by directly acting on the cardiomyocyte to reverse hypertrophy. The effect of HHQ16 was associated with a strong inhibition of a newly discovered Egr2-affiliated transcript lnc9456 in the heart. While minimally expressed in normal mouse heart, lnc9456 was dramatically upregulated in the heart subjected to left anterior descending coronary artery ligation (LADL) and in cardiomyocytes subjected to hypertrophic stimulation. The critical role of lnc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro. A physical interaction between lnc9456 and G3BP2 increased NF-κB nuclear translocation, triggering hypertrophy-related cascades. HHQ16 physically bound to lnc9456 with a high-affinity and induced its degradation. Cardiomyocyte-specific lnc9456 overexpression induced, but knockout prevented LADL-induced, cardiac hypertrophy and dysfunction. HHQ16 reversed the effect of lnc9456 overexpression while lost its protective role when lnc9456 was deleted, further confirming lnc9456 as the bona fide target of HHQ16. We further identified the human ortholog of lnc9456, also an Egr2-affiliated transcript, lnc4012. Similarly, lnc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy. HHQ16 also specifically bound to lnc4012 and caused its degradation and antagonized its hypertrophic effects. Targeted degradation of pathological increased lnc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF.
(© 2023. West China Hospital, Sichuan University.)
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المشرفين على المادة: 3A592W8XKE (astragaloside A)
تواريخ الأحداث: Date Created: 20231019 Date Completed: 20231023 Latest Revision: 20231122
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10587311
DOI: 10.1038/s41392-023-01660-9
PMID: 37857609
قاعدة البيانات: MEDLINE
الوصف
تدمد:2059-3635
DOI:10.1038/s41392-023-01660-9