Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy
Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy
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四氢小檗红素通过促进 PHB2 介导的线粒体自噬延缓小鼠心脏衰老
DOI：
10.1038/s41401-022-00956-w
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发表时间：
2022-08
影响因子：
8.2
通讯作者：
Yong Zhang
中科院分区：
文献类型：
--
作者：
Lei Wang;Xue-Qing Tang;Yang Shi;Hui-Min Li;Zi-Yu Meng;Hui Chen;Xiao-Han Li;Yong-Chao Chen;Heng Liu;Yang Hong;Heng-Hui Xu;Ling Liu;Limin Zhao;Wei-Na Han;Xin Liu;Yong Zhang
心脏老化以左室肥厚和舒张功能不全为特征，进而诱发多种心血管疾病。目前还没有治疗性药物可以改善心脏衰老过程中的心脏异常。本研究探讨了小檗碱（BBR）及其衍生物四氢小檗碱（THBru）对心脏衰老过程的保护作用。采用d-半乳糖（D-gal, 120 mg·kg-1·d-1, sc.）连续12周诱导小鼠心脏老化。同时，小鼠口服小檗碱（50 mg·kg-1·d-1）或THBru(25、50 mg·kg-1·d-1) 12周。我们发现，BBR和THBru治疗可显著减轻d -gal诱导的衰老小鼠的舒张功能障碍和心脏重塑。此外，BBR （40 μM）和THBru（20、40 μM）处理可抑制d -gal诱导的原代新生小鼠心肌细胞体外衰老。总体而言，在相同剂量下，THBru的疗效高于BBR。我们发现，在体内和体外衰老过程中，线粒体自噬水平显著降低，THBru和BBR对线粒体自噬的促进作用不同。我们证明THBru诱导线粒体自噬的作用是由于抑制素2 (PHB2) mRNA的稳定性增加，从而上调PHB2蛋白的表达。PHB2是线粒体自噬过程中的关键因子。在d -gal处理的心肌细胞中，敲低PHB2可有效逆转THBru的抗衰老作用。相反，与THBru一样，过表达PHB2促进线粒体自噬，延缓心肌细胞衰老。综上所述，本研究确定THBru是一种诱导phb2介导的线粒体自噬的有效抗衰老药物，并提出了其临床应用前景。
Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg-1 · d-1, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg-1 · d-1) or THBru (25, 50 mg · kg-1 · d-1) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 μM) and THBru (20, 40 μM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated mitophagy and suggests its clinical application prospects.
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影响因子：
64.5
作者：
Wei Y;Chiang WC;Sumpter R Jr;Mishra P;Levine B
通讯作者：
Levine B
影响因子：
5
作者：
Horn MA;Trafford AW
通讯作者：
Trafford AW
小檗碱通过调节 p16 和细胞周期蛋白表达改善细胞衰老并延长小鼠寿命
影响因子：
7.8
作者：
Dang, Yao;An, Yongpan;Xie, Zhengwei
通讯作者：
Xie, Zhengwei
影响因子：
3.6
作者：
Liguori I;Russo G;Curcio F;Bulli G;Aran L;Della-Morte D;Gargiulo G;Testa G;Cacciatore F;Bonaduce D;Abete P
通讯作者：
Abete P
DOI：
10.1016/j.jnutbio.2019.108261
发表时间：
2019-10
期刊：
The Journal of nutritional biochemistry
影响因子：
--
作者：
Che Wang;Zhengxu Cai;Wei Wang;Min Wei;Xinhong Si;Yuting Shang;Zhaofei Yang;Tianbai Li
通讯作者：
Che Wang;Zhengxu Cai;Wei Wang;Min Wei;Xinhong Si;Yuting Shang;Zhaofei Yang;Tianbai Li