Fibroblast growth factor 21 protects the heart from angiotensin II-induced cardiac hypertrophy and dysfunction via SIRT1
Fibroblast growth factor 21 protects the heart from angiotensin II-induced cardiac hypertrophy and dysfunction via SIRT1
复制标题
成纤维细胞生长因子 21 通过 SIRT1 保护心脏免受血管紧张素 II 诱导的心脏肥大和功能障碍
DOI：
10.1016/j.bbadis.2019.01.019
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发表时间：
2019-06-01
影响因子：
6.2
通讯作者：
Jin, Litai
中科院分区：
文献类型：
--
作者：
Li, Santie;Zhu, Zhongxin;Jin, Litai
目的：探讨成纤维细胞生长因子21(FGF21)对血管紧张素II(Ang 11)诱导的心肌肥大和功能障碍的保护作用机制。方法：8~12周龄雄性沉默信息调节因子1(SIRT1)FLOX/FLOX和心肌细胞特异性诱导型SIRT1基因敲除小鼠(SIRT1-iK0)，给予Ang II(1.1 mg/kg/d，连续4周)治疗。FGF21治疗[2.5 mg/kg/d，连续4周，腹腔注射]。注射)与血管紧张素II输注同时开始。在体外实验中，新生大鼠心肌细胞(NRCM)、H9c2大鼠心肌细胞和分离的成年小鼠心肌细胞分别用Ang II(1 NM)和FGF21(20 NM)处理24 h，同时或不加SIRT1沉默。结果：FGF21治疗可明显减轻Ang II诱导的心肌肥大和功能障碍。SIRT1基因敲除取消了FGF21预防Ang 11诱导的心肌肥大、纤维化和细胞凋亡的能力，但不影响FGF21在Ang II诱导的高血压中的有益作用，也不影响高血压本身。FGF21能显著增强SIRT1的脱乙酰酶活性，促进SIRT1与肝激酶BI(LKB1)和叉头盒蛋白01(Fox01)的相互作用，从而降低SIRT1靶蛋白的乙酰化水平。因此，FGF21促进LKB1靶基因AMPK的激活，并改变FOX01在其下游靶基因过氧化氢酶(Cat)、锰超氧化物歧化酶(Sod2)和Bim上的转录活性，从而减少活性氧(ROS)积累和心肌细胞凋亡。结论：FGF21以SIRT1依赖的方式改善心功能，减轻Ang II诱导的心肌肥厚。
Aims: This study investigated the mechanism through which fibroblast growth factor 21 (FGF21) protects against angiotensin II (Ang 11)-induced cardiac hypertrophy and dysfunction. Methods: Male silent information regulator 1 (SIRT1) fiox/flox and cardiomyocyte-specific inducible SIRT1 knockout mice (SIRT1-iK0) were generated and treated with Ang II (1.1 mg/kg/day for 4 weeks) at the age of 8-12-week-old. FGF21 treatment [2.5 mg/kg/day for 4 weeks by intraperitoneal (i.p.) injection) was initiated at the same time as the Ang II infusion. For in vitro studies, neonatal rat cardiomyocytes (NRCMs), H9c2 rat cardiomyocytes and isolated adult mouse cardiomyocytes were treated with Ang II (1 NM) and FGF21 (20 nM) for 24 h with or without SIRT1 silencing. Results: FGF21 treatment significantly attenuated Ang II-induced cardiac hypertrophy and dysfunction. SIRT1 knockout abolished the ability of FGF21 to prevent Ang 11-induced cardiac hypertrophy, fibrosis, and apoptosis, without affecting the beneficial effects of FGF21 in Ang II-induced hypertension, and did not influence the hypertension itself. FGF21 markedly increased the deacetylase activity of SIRT1 and promoted the interaction of SIRT1 with liver kinase BI (LKB1) and forkhead box protein 01 (FoxOl), resulting in decreased acetylation of these SIRT1 target proteins. Consequently, FGF21 promoted the activation of the LKB1 target adenosine monophosphate-activated protein kinase (AMPK) and altered the transcriptional activity of Fox01 on its downstream target genes catalase (Cat), MnSOD (Sod2), and Bim, resulting in reduced reactive oxygen species (ROS) accumulation and cardiomyocyte apoptosis. Conclusions: FGF21 improves cardiac function and alleviates Ang II-induced cardiac hypertrophy in a SIRT1dependent manner.