Zeng Heng, He Xiaochen, Tuo Qin-Hui, Liao Duan-Fang, Zhang Guo-Qiang, Chen Jian-Xiong
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, 39216, USA.
School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
Sci Rep. 2016 Feb 12;6:20931. doi: 10.1038/srep20931.
Recent studies reveal a crucial role of pericyte loss in sepsis-associated microvascular dysfunction. Sirtuin 3 (SIRT3) mediates histone protein post-translational modification related to aging and ischemic disease. This study investigated the involvement of SIRT3 in LPS-induced pericyte loss and microvascular dysfunction. Mice were exposed to LPS, expression of Sirt3, HIF-2α, Notch3 and angiopoietins/Tie-2, pericyte/endothelial (EC) coverage and vascular permeability were assessed. Mice treated with LPS significantly reduced the expression of SIRT3, HIF-2α and Notch3 in the lung. Furthermore, exposure to LPS increased Ang-2 while inhibited Ang-1/Tie-2 expression with a reduced pericyte/EC coverage. Intriguingly, knockout of Sirt3 upregulated Ang-2, but downregulated Tie-2 and HIF-2α/Notch3 expression which resulted in a dramatic reduction of pericyte/EC coverage and exacerbation of LPS-induced vascular leakage. Conversely, overexpression of Sirt3 reduced Ang-2 expression and increased Ang-1/Tie-2 and HIF-2α/Notch3 expression in the LPS treated mice. Overexpression of Sirt3 further prevented LPS-induced pericyte loss and vascular leakage. This was accompanied by a significant reduction of the mortality rate. Specific knockout of prolyl hydroxylase-2 (PHD2) increased HIF-2α/Notch3 expression, improved pericyte/EC coverage and reduced the mortality rate in the LPS-treated mice. Our study demonstrates the importance of SIRT3 in preserving vascular integrity by targeting pericytes in the setting of LPS-induced sepsis.
近期研究揭示了周细胞丢失在脓毒症相关微血管功能障碍中的关键作用。沉默调节蛋白3（SIRT3）介导与衰老和缺血性疾病相关的组蛋白翻译后修饰。本研究调查了SIRT3在脂多糖（LPS）诱导的周细胞丢失和微血管功能障碍中的作用。将小鼠暴露于LPS，评估Sirt3、缺氧诱导因子-2α（HIF-2α）、Notch3以及血管生成素/Tie-2的表达、周细胞/内皮细胞（EC）覆盖率和血管通透性。用LPS处理的小鼠肺组织中SIRT3、HIF-2α和Notch3的表达显著降低。此外，暴露于LPS会增加血管生成素-2（Ang-2），同时抑制血管生成素-1（Ang-1）/Tie-2的表达，导致周细胞/EC覆盖率降低。有趣的是，敲除Sirt3会上调Ang-2，但下调Tie-2以及HIF-2α/Notch3的表达，这导致周细胞/EC覆盖率显著降低，并加剧LPS诱导的血管渗漏。相反，在经LPS处理的小鼠中过表达Sirt3会降低Ang-2的表达，并增加Ang-1/Tie-2以及HIF-2α/Notch3的表达。Sirt3过表达进一步预防了LPS诱导的周细胞丢失和血管渗漏。这伴随着死亡率的显著降低。脯氨酰羟化酶-2（PHD2）的特异性敲除增加了HIF-2α/Notch3的表达，改善了周细胞/EC覆盖率，并降低了经LPS处理小鼠的死亡率。我们的研究证明了SIRT3在LPS诱导的脓毒症情况下通过靶向周细胞来维持血管完整性的重要性。
