Crucial role of hyaluronan in neointimal formation after vascular injury.
Crucial role of hyaluronan in neointimal formation after vascular injury.
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DOI：
10.1371/journal.pone.0058760
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ikeda U
中科院分区：
文献类型：
--
作者：
Kashima Y;Takahashi M;Shiba Y;Itano N;Izawa A;Koyama J;Nakayama J;Taniguchi S;Kimata K;Ikeda U
透明质酸（HA）是细胞外基质的主要成分，参与动脉粥样硬化的发病机制。本研究的目的是探讨HA在血管损伤后新生内膜形成中的作用，并通过使用cre-lox条件转基因（cTg）策略确定其在血管平滑肌细胞（VSMCs）中的组织特异性作用。HA在动脉粥样硬化患者的新生内膜病变和小鼠的导丝介导的血管损伤中表达。使用4-甲基伞形酮抑制HA合成可显著抑制损伤后新生内膜形成。体外实验表明，低分子量HA（LMW-HA）诱导VSMC活化，包括迁移，增殖，产生炎性细胞因子和活性氧（ROS）。CD 44/RhoA和CD 44/ERK 1/2通路分别介导VSMCs的迁移和增殖。由于HA合酶2（HAS 2）主要在受损动脉中表达，我们产生了在VSMC中特异性过表达鼠HAS 2基因的cTg小鼠（cHAS 2/CreSM 22 α小鼠），并显示HA过表达显著增强了袖套介导的血管损伤后的新生内膜形成。此外，从cHAS 2/CreSM 22 α小鼠中分离的HA过表达VSMC显示出增强的迁移、增殖和炎性细胞因子和ROS的产生。VSMC来源的HA促进血管损伤后的新生内膜形成，并且HA可能是心血管疾病的潜在治疗靶点。
Hyaluronan (HA) is a primary component of the extracellular matrix of cells, and it is involved in the pathogenesis of atherosclerosis. The purpose of this study was to investigate the role of HA in neointimal formation after vascular injury and determine its tissue-specific role in vascular smooth muscle cells (VSMCs) by using a cre-lox conditional transgenic (cTg) strategy. HA was found to be expressed in neointimal lesions in humans with atherosclerosis and after wire-mediated vascular injury in mice. Inhibition of HA synthesis using 4-methylumbelliferone markedly inhibited neointimal formation after injury. In vitro experiments revealed that low-molecular-weight HA (LMW-HA) induced VSMC activation, including migration, proliferation, and production of inflammatory cytokines, and reactive oxygen species (ROS). The migration and proliferation of VSMCs were mediated by the CD44/RhoA and CD44/ERK1/2 pathways, respectively. Because HA synthase 2 (HAS2) is predominantly expressed in injured arteries, we generated cTg mice that overexpress the murine HAS2 gene specifically in VSMCs (cHAS2/CreSM22α mice) and showed that HA overexpression markedly enhanced neointimal formation after cuff-mediated vascular injury. Further, HA-overexpressing VSMCs isolated from cHAS2/CreSM22α mice showed augmented migration, proliferation, and production of inflammatory cytokines and ROS. VSMC-derived HA promotes neointimal formation after vascular injury, and HA may be a potential therapeutic target for cardiovascular disease.
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影响因子：
33.6
作者：
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通讯作者：
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发表时间：
2002-10-01
影响因子：
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作者：
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通讯作者：
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