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Astragaloside IV derivative HHQ16 ameliorates infarctioninduced hypertrophy and heart failure through degradation of lncRNA4012/9456

查看全文 作　　者：Jingjing [1]Wan;Zhen [1]Zhang;hennan [1]Wu;Saisai Tianbei [1]Zang;Ge [1]Jin;Qingyan [2]Sun;Pin [3]Wang;Xin [4]Luan;Yili [5]Yang;Xuelin [5,6]Zhan;Lingyu Linda [7]Ye;Dayue Darrel [7,8]Duan;Xia [1]Liu;Weidong [1,9]Zhang 高影响力作者 机构地区：[1]School of Pharmacy,Second Miltary Medical University,Shanghai,PR China;[2]China Institute of Pharmaceutical Industry,Shanghai,PR China;[3]Key Laboratory of Medical Immunology and Institute of Immunology,Second Military Medical University,Shanghai,PR China;[4]Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai,PR China;[5]China Regional Research Centre,International Centre of Genetic Engineering&Biotechnology,Taizhou,PR China;[6]State Key Laboratory of Medicinal Chemical Biology,College of Pharmacy,Nankai University,Tianjin,PR China;[7]Center for Phenomics of Traditional Chinese Medicine,Hospital of Traditional Chinese Medicine Affliated to Southwest Medical University,Southwest Medical University,Luzhou,PR China;[8]Key Laboratory of Autoimmune Diseases and Precision Medicine,People's Hospital of Ningxia Hui Autonomous Region,Yinchuan,PR China;[9]Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,PR China高影响力机构 出　　处：《Signal Transduction and Targeted Therapy》索引2023年第8卷第11期,共16页高影响力期刊 基　　金：National Natural Science Foundation of China(82141203,82073842 and 82273920);Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTDD-202004);Shanghai Scientific and Innovative Action Plan(21XD1404700);the Science and Technology strategic cooperation Programs of Luzhou Municipal People's Government and Southwest Medical University(2017LZXNYD-P01,2019 LZXNYD-PO1DUAN). 摘　　要：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-affliated transcript Inc9456 in the heart.While minimally expressed in normal mouse heart,Inc9456 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 Inc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro.A physical interaction between Inc9456 and G3BP2 increased NF-kB nuclear translocation,triggering hypertrophy-related cascades.HHQ16 physically bound to Inc9456 with a high-affinity and induced its degradation.Cardiomyocyte-specific Inc9456 overexpression induced,but knockout prevented LADL-induced,cardiac hypertrophy and dysfunction.HHQ16 reversed the effect of Inc9456 overexpression while lost its protective role when Inc9456 was deleted,further confirming Inc9456 as the bona fide target of HHQ16.We further identified the human ortholog of Inc9456,also an Egr2-affliated transcript,Inc4012.Similarly,Inc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy.HHQ16 also specifically bound to Inc4012 and caused its degradation and antagonized its hypertrophic effects.Targeted degradation of pathological increased Inc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF. 关 键 词：HYPERTROPHY INFARCTION protective
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