Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3
Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3
复制标题
盐诱导的肝脏炎症记忆通过 SIRT3 的表观遗传调节导致心血管损伤
DOI：
10.1161/circulationaha.121.055600
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发表时间：
2022-02-01
期刊：
影响因子：
37.8
通讯作者：
Zhu, Zhiming
中科院分区：
文献类型：
--
作者：
Gao, Peng;You, Mei;Zhu, Zhiming
背景：高盐摄入量是心血管疾病的主要饮食危险因素。尽管临床证据表明高盐摄入与非酒精性脂肪肝相关，而非酒精性脂肪肝是心血管疾病的独立危险因素，但盐引起的肝损伤是否会导致心血管疾病的发生仍不清楚。方法：用正常或高盐饮食喂养小鼠8周，测定盐负荷对肝脏组织学变化和血压的影响，并对部分高盐饮食喂养的小鼠进行戒盐和二甲双胍治疗。使用腺相关病毒8、全局敲除或组织特异性敲除小鼠来操纵体内一些靶基因的表达，包括SIRT3（sirtuin 3）、NRF2（NF-E2相关因子2）和AMPK（AMP激活蛋白激酶）。结果：高盐饮食喂养的小鼠出现明显的肝脏脂肪变性和炎症，并伴有高血压和心功能不全。所有这些病理变化在戒盐后仍持续存在，表现出记忆现象。 SIRT3敲除小鼠的基因表达分析和表型显示，SIRT3表达减少是造成肝脏持续炎症的罪魁祸首，恢复肝脏中SIRT3的表达可有效抑制持续的肝脏炎症和心血管损伤。机制研究表明，高盐会增加肝细胞SIRT3启动子上的乙酰化组蛋白3赖氨酸27（H3K27ac），从而抑制NRF2的结合，导致SIRT3表达持续抑制。二甲双胍治疗可激活 AMPK，通过降低 SIRT3 启动子上的 H3K27ac 水平来抑制盐诱导的肝脏炎症记忆和心血管损伤，并增加 NRF2 结合能力以激活 SIRT3 表达。结论：本研究表明，组蛋白修饰引起的 SIRT3 抑制是高盐负荷下持续性肝脂肪变性和炎症导致心血管损伤的关键因素。在临床实践中，避免过量盐摄入和积极干预表观遗传修饰可能有助于避免高盐诱发心血管损伤的持续炎症状态。
Background: High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases. Methods: Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet-fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase). Results: Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression. Conclusions: This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt-induced cardiovascular damage in clinical practice.