| 1 | Astragaloside IV derivative HHQ16 ameliorates infarctioninduced hypertrophy and heart failure through degradation of lncRNA4012/9456显示文摘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. | Jingjing Wan Zhen Zhang hennan Wu Saisai Tianbei Zang Ge Jin Qingyan Sun Pin Wang Xin Luan Yili Yang Xuelin Zhan Lingyu Linda Ye Dayue Darrel Duan Xia Liu Weidong Zhang | 2023 | Signal Transduction and Targeted Therapy2023，8，11： | 0 |
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