Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation.
Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation.
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DOI：
10.1016/j.avsg.2017.10.001
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发表时间：
2018-01
影响因子：
1.5
通讯作者：
Ruddy JM
中科院分区：
文献类型：
--
作者：
Akerman AW;Stroud RE;Barrs RW;Grespin RT;McDonald LT;LaRue RAC;Mukherjee R;Ikonomidis JS;Jones JA;Ruddy JM
高血压（HTN）长期以来与腹主动脉瘤（AAA）的发展相关，并且这些心血管病理的生化特征在于血管紧张素II（AngII）以及白细胞介素-6（IL-6）的血浆水平升高。然而，HTN和AAA之间的生物学关系尚未建立。因此，本研究的目的是评估升高的张力是否可以启动IL-6的产生以积聚单核细胞/巨噬细胞并促进腹主动脉（AA）的扩张。使用渗透输注泵建立IL-6输注模型（4.36 µg/kg/天），4周后，通过数字显微镜测量AA直径。然后切除AA进行CD 68免疫染色和用CD 11b和F4/80进行流式细胞术分析以鉴定巨噬细胞。将来自野生型小鼠的主动脉节段以实验得出的最佳张力（1.2g）和升高的张力（ET，1.7g）悬浮在离体组织肌描记器中的平行线上3小时，并通过定量聚合酶链反应（QPCR）评价IL-6和单核细胞趋化蛋白-1（MCP-1）的表达。使分离的主动脉血管平滑肌细胞（VSMC）经受12%双轴循环拉伸或保持静止（对照）3小时（n = 7），并通过QPCR评估IL-6和MCP-1表达。4周IL-6输注导致AA外径比对照小鼠大72.5 ± 5.6%（P < 0.05），并且主动脉扩张伴随着AA中层中巨噬细胞的积聚，如通过CD 68+染色增加以及通过流式细胞术定量的CD 11b +/F4/80+细胞增加所定义的。野生型AA节段对ET的离体应用无反应，但与静态对照相比，分离的VSMCs的周期性拉伸增加了IL-6（2.03 ± 0.3倍）和MCP-1（1.51 ± 0.11倍）的表达（P < 0.05）。在这两种情况下，用选择性STAT 3抑制剂WP 1066预处理减弱了反应。有趣的是，AngII没有刺激IL-6和MCP-1的表达高于由张力引发的表达，并且再次，该反应被WP 1066抑制，支持STAT 3在该途径中的整体作用。IL-6输注模型可以启动巨噬细胞积聚以及主动脉扩张，并且在张力升高的条件下，这种促炎细胞因子可以由主动脉VSMC产生。通过STAT 3的激活，MCP-1表达以增加培养基巨噬细胞丰度并产生对扩张敏感的环境。HTN和主动脉扩张之间的这种生物力学关联可能有助于识别新的治疗策略。
Hypertension (HTN) has long been associated with abdominal aortic aneurysm (AAA) development, and these cardiovascular pathologies are biochemically characterized by elevated plasma levels of angiotensin II (AngII) as well as interleukin-6 (IL-6). A biologic relationship between HTN and AAA has not been established, however. Accordingly, the objective of this study was to evaluate whether elevated tension may initiate IL-6 production to accumulate monocyte/macrophages and promote dilation of the abdominal aorta (AA). An IL-6 infusion model (4.36 µg/kg/day) was created utilizing an osmotic infusion pump, and after 4 weeks, AA diameter was measured by digital microscopy. The AA was then excised for CD68 immunostaining and flow cytometric analysis with CD11b and F4/80 to identify macrophages. Aortic segments from wild-type mice were suspended on parallel wires in an ex vivo tissue myograph at experimentally derived optimal tension (1.2 g) and in the presence of elevated tension (ET, 1.7 g) for 3 hr, and expression of IL-6 and monocyte chemoattractant protein-1 (MCP-1) was evaluated by quantitative polymerase chain reaction (QPCR). Isolated aortic vascular smooth muscle cells (VSMCs) were subjected to 12% biaxial cyclic stretch or held static (control) for 3 hr (n = 7), and IL-6 and MCP-1 expressions were evaluated by QPCR. Four-week IL-6 infusion resulted in an AA outer diameter that was 72.5 ± 5.6% (P < 0.05) greater than that of control mice, and aortic dilation was accompanied by an accumulation of macrophages in the AA medial layer as defined by an increase in CD68 + staining as well as an increase by flow cytometric quantification of CD11b+/F4/80+ cells. Wild-type AA segments did not respond to ex vivo application of ET but cyclic stretch of isolated VSMCs increased IL-6 (2.03 ± 0.3 fold) and MCP-1 (1.51 ± 0.11 fold) expression compared to static control (P < 0.05). Pretreatment with the selective STAT3 inhibitor WP1066 blunted the response in both cases. Interestingly, AngII did not stimulate expression of IL-6 and MCP-1 above that initiated by tension and again, the response was inhibited by WP1066, supporting an integral role of STAT3 in this pathway. An IL-6 infusion model can initiate macrophage accumulation as well as aortic dilation, and under conditions of elevated tension, this proinflammatory cytokine can be produced by aortic VSMCs. By activation of STAT3, MCP-1 is expressed to increase media macrophage abundance and create an environment susceptible to dilation. This biomechanical association between HTN and aortic dilation may allow for the identification of novel therapeutic strategies.
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