Lipid phosphate phosphatase 3 negatively regulates smooth muscle cell phenotypic modulation to limit intimal hyperplasia.
Lipid phosphate phosphatase 3 negatively regulates smooth muscle cell phenotypic modulation to limit intimal hyperplasia.
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DOI：
10.1161/atvbaha.112.300527
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Smyth SS
中科院分区：
文献类型：
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作者：
Panchatcharam M;Miriyala S;Salous A;Wheeler J;Dong A;Mueller P;Sunkara M;Escalante-Alcalde D;Morris AJ;Smyth SS
脂质磷酸磷酸酶3（LPP 3）降解生物活性溶血磷脂，包括溶血磷脂酸（LPA）和鞘氨醇-1-磷酸（S1 P），从而终止它们的信号传导作用。虽然新出现的证据将LPA与动脉粥样硬化和血管损伤反应联系起来，但对血管LPP 3的作用知之甚少。本研究的目的是确定LPP 3在血管新生内膜形成和平滑肌细胞（SMC）反应的发展中的作用。我们报道了实验性动脉损伤后LPP 3在血管SMC中表达。使用增益和功能丧失的方法，我们建立了一个主要的功能，LPP 3在分离的SMC细胞是减弱增殖，（ERK）活性，Rho激活，并响应于血清和LPA的迁移。这些效应至少部分是LPP 3催化的LPA水解的结果。SMC中LPP 3选择性失活的小鼠显示出对损伤的过度新生内膜反应。我们的观察结果表明，LPP 3作为一个内在的负调节SMC表型调制和炎症血管损伤后，部分通过调节溶血磷脂信号。这些发现可能为解释PPAP 2B多态性与冠状动脉疾病风险之间的关联提供了一种机制联系。
The lipid phosphate phosphatase 3 (LPP3) degrades bioactive lysophospholipids including lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) and thereby terminates their signaling effects. While emerging evidence links LPA to atherosclerosis and vascular injury responses, little is known about the role of vascular LPP3. The goal of this study was to determine the role of LPP3 in the development of vascular neointima formation and smooth muscle cells (SMC) responses. We report that LPP3 is expressed in vascular SMC following experimental arterial injury. Using gain- and loss-of-function approaches, we establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation, (ERK) activity, Rho activation, and migration in response to serum and LPA. These effects are at least partially a consequence of LPP3-catalyzed LPA hydrolysis. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to injury. Our observations suggest that LPP3 serves as an intrinsic negative regulator of SMC phenotypic modulation and inflammation after vascular injury, in part by regulating lysophospholipid signaling. These findings may provide a mechanistic link to explain the association between a PPAP2B polymorphism and coronary artery disease risk.