SIRT3 (Sirtuin-3) Prevents Ang II (Angiotensin II)-Induced Macrophage Metabolic Switch Improving Perivascular Adipose Tissue Function
SIRT3 (Sirtuin-3) Prevents Ang II (Angiotensin II)-Induced Macrophage Metabolic Switch Improving Perivascular Adipose Tissue Function
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DOI：
10.1161/atvbaha.120.315337
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发表时间：
2021-02-01
影响因子：
8.7
通讯作者：
Shen, Weili
中科院分区：
文献类型：
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作者：
Wei, Tong;Gao, Jing;Shen, Weili
目的：浸润性巨噬细胞积极促进血管周围脂肪组织重塑，在高血压小鼠血管周围脂肪组织微环境中占优势群体。然而，巨噬细胞在引发代谢性炎症中的作用仍不确定。SIRT3 （sirtuin-3）是一种nad依赖性的去乙酰化酶，对代谢状态敏感并介导适应反应。在这项研究中，我们研究了sirt3介导的代谢转移在调节NLRP3 （nod样受体家族pyrin结构域3）炎症小体激活中的作用。方法和结果：在这里，我们报道了Ang II（血管紧张素II）加速血管周围脂肪组织炎症和纤维化，伴随着NLRP3炎性体激活和IL（白细胞介素）-1 β分泌，在髓系SIRT3敲除（-/）（-）小鼠中。这种效应与脂肪组织线粒体功能障碍有关。体外研究表明，骨髓源性巨噬细胞中SIRT3的缺失通过将代谢表型从氧化磷酸化转变为糖酵解来诱导IL-1 β的产生。从机制上讲，SIRT3在赖氨酸83处脱乙酰并激活PDHA1（丙酮酸脱氢酶E1 α）， SIRT3的缺失导致PDH活性降低和乳酸积累。降低LDHA（乳酸脱氢酶A）或使用肌肽（一种对抗乳酸的缓冲物），会减弱IL-1 β的分泌。此外，阻断巨噬细胞进入棕色脂肪细胞的IL-1 β可恢复产热标志物和线粒体耗氧量。此外，NLRP3基因敲除（NLRP3(-/-)）小鼠表现出IL-1 β产生减少，同时挽救棕色脂肪细胞的线粒体功能，减轻血管周围脂肪组织纤维化。结论：SIRT3是减轻nlrp3相关炎症的潜在治疗靶点。糖酵解代谢的药物靶向可能是一种有效的治疗方法。
Objective:Infiltrated macrophages actively promote perivascular adipose tissue remodeling and represent a dominant population in the perivascular adipose tissue microenvironment of hypertensive mice. However, the role of macrophages in initiating metabolic inflammation remains uncertain. SIRT3 (sirtuin-3), a NAD-dependent deacetylase, is sensitive to metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated metabolic shift in regulating NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome activation.Approach and Results:Here, we report that Ang II (angiotensin II) accelerates perivascular adipose tissue inflammation and fibrosis, accompanied by NLRP3 inflammasome activation and IL (interleukin)-1 beta secretion in myeloid SIRT3 knockout (SIRT3(-/)(-)) mice. This effect is associated with adipose tissue mitochondrial dysfunction. In vitro studies indicate that the deletion of SIRT3 in bone marrow-derived macrophages induces IL-1 beta production by shifting the metabolic phenotype from oxidative phosphorylation to glycolysis. Mechanistically, SIRT3 deacetylates and activates PDHA1 (pyruvate dehydrogenase E1 alpha) at lysine 83, and the loss of SIRT3 leads to PDH activity decrease and lactate accumulation. Knocking down LDHA (lactate dehydrogenase A) or using carnosine, a buffer against lactic acid, attenuates IL-1 beta secretion. Furthermore, the blockade of IL-1 beta from macrophages into brown adipocytes restores thermogenic markers and mitochondrial oxygen consumption. Moreover, NLRP3 knockout (NLRP3(-/-)) mice exhibited reduced IL-1 beta production while rescuing the mitochondrial function of brown adipocytes and alleviating perivascular adipose tissue fibrosis.Conclusions:SIRT3 represents a potential therapeutic target to attenuate NLRP3-related inflammation. Pharmacological targeting of glycolytic metabolism may represent an effective therapeutic approach.