Upregulation of angiostatic chemokines IP-10/CXCL10 and I-TAC/CXCL11 in human obesity and their implication for adipose tissue angiogenesis
Upregulation of angiostatic chemokines IP-10/CXCL10 and I-TAC/CXCL11 in human obesity and their implication for adipose tissue angiogenesis
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血管抑制趋化因子IP-10/CXCL 10和I-TAC/CXCL 11在人类肥胖中的上调及其对脂肪组织血管生成的影响
DOI：
10.1038/s41366-018-0102-5
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发表时间：
2018-08-01
影响因子：
4.9
通讯作者：
Piqueras, Laura
中科院分区：
文献类型：
--
作者：
Hueso, Luisa;Ortega, Rebeca;Piqueras, Laura
背景/目的：在人类肥胖症中，血管生成受损与脂肪组织（AT）功能障碍、炎症和胰岛素抵抗有关。趋化因子（C-X-C基序）受体。CXCR 3配体是不同疾病背景如癌症中血管生成的重要调节剂;然而，它们在人类病态肥胖中的作用尚不清楚。我们研究了CXCR 3轴在病态肥胖患者AT血管生成中的作用。受试者/方法：研究组包括50例病态肥胖患者（平均年龄44 +/- 1岁，体重指数44 +/- 1 kg/m2），他们接受了腹腔镜Roux-Y胃旁路手术，25例年龄匹配的非肥胖对照组。我们在所有研究对象中测量了由干扰素-γ（IFN-γ/CXCL 9）、干扰素-γ诱导蛋白10（IP-10/CXCL 10）和干扰素-γ诱导T细胞α化学引诱物（I-TAC/CXCL 11）诱导的CXCR 3配体单核因子的循环水平。此外，在病态肥胖患者腹腔镜手术期间获得的皮下和内脏AT配对活检中分析CXCR 3配体的表达。此外，我们探索了CXCR 3配体对血管生成的功能作用，在AT从病态肥胖patients.Results：血浆水平的CXCL 10和CXCL 11是病态肥胖患者显著高于对照组（p < 0.01）。在离体测定中，内脏AT中的血管生成生长显著低于皮下AT（p < 0.05），这与CXCL 10、CXCL 11和CXCR 3的显著组织上调有关（p < 0.05）。CXCL 10或CXCL 11抑制AT血管生成（p < 0.05），并且阻断CXCR 3功能显著增加内脏脂肪沉积中的毛细血管发芽（p < 0.05）。Western blot分析显示，p38丝裂原活化蛋白激酶信号通路参与了CXCR 3对AT的血管抑制作用。结论：CXCL 10和CXCL 11可能参与了AT的血管抑制作用。作为AT血管生成的潜在抑制剂，在肥胖症中起有害作用。因此，CXCR 3的药理学阻断可以代表。治疗，以防止AT功能障碍的肥胖。
Background/Aims: Impaired angiogenesis is linked to adipose tissue (AT) dysfunction, inflammation, and insulin resistance in human obesity. Chemokine (C-X-C motif) receptor. (CXCR3) ligands are important regulators of angiogenesis in different disease contexts such as cancer; however, their role in human morbid obesity is unknown. We investigated the role of the CXCR3 axis in AT angiogenesis in morbidly obese patients.Subjects/Methods: The study group comprised 50 morbidly obese patients (mean age 44 +/- 1 years, body mass index 44 +/- 1 kg/m(2)) who had undergone laparoscopic Roux-Y-gastric bypass surgery, and 25 age-matched non-obese control subjects. We measured the circulating levels of the CXCR3 ligands monokine induced by interferon-gamma (MIG/CXCL9), interferon-gamma inducible protein 10 (IP-10/CXCL10), and interferon-gamma-inducible T-cell alpha chemoattractant (I-TAC/CXCL11) in all studied subjects. Additionally, the expression of CXCR3 ligands was analyzed in paired biopsies of subcutaneous and visceral AT obtained during the laparoscopic procedure in morbidly obese patients. Additionally, we explored the functional role of CXCR3 ligands on angiogenesis in AT from morbidly obese patients using an ex vivo assay.Results: Plasma levels of CXCL10 and CXCL11 were significantly higher in morbidly obese patients than in controls (p < 0.01). In ex vivo assays, angiogenic growth was markedly lower in visceral AT than in subcutaneous AT (p < 0.05), which was related to significant tissue upregulation of CXCL10, CXCL11 and CXCR3 (p < 0.05). CXCL10 or CXCL11 inhibited AT angiogenesis (p < 0.05), and blockade of CXCR3 function significantly increased capillary sprouting in visceral fat deposits (p < 0.05). Western blot analysis showed that the p38 mitogen-activated protein kinase signaling pathway was implicated in the angiostatic effects of CXCR3 in AT.Conclusions: CXCL10 and CXCL11 may play. deleterious role in obesity as potential inhibitors of AT angiogenesis. Accordingly, pharmacological blockade of CXCR3 could represent. therapy to prevent AT dysfunction in obesity.