Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake
Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake
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DOI：
10.1074/jbc.m701638200
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发表时间：
2007-05-25
影响因子：
4.8
通讯作者：
Roberts, David D.
中科院分区：
文献类型：
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作者：
Isenberg, Jeff S.;Jia, Yifeng;Roberts, David D.
尽管 CD36 通常被认为是血小板反应蛋白-1 (TSP1) 的抑制性信号受体，但该信号转导的分子机制仍不清楚。基于肉豆蔻酸和 TSP1 各自以 CD36 依赖性方式调节内皮细胞一氧化氮信号传导的证据，我们检查了 TSP1 调节 CD36 脂肪酸转位酶活性的能力。 TSP1 和模拟 TSP1 活性的 CD36 抗体抑制肉豆蔻酸的摄取。重组 TSP1 1 型重复序列具有弱抑制作用，但源自该结构域的抗血管生成肽可有效抑制肉豆蔻酸的摄取。该肽还抑制肉豆蔻酰化 CD36 信号靶标 Fyn 的膜易位和 Src 家族激酶的激活。肉豆蔻酸的摄取通过内皮一氧化氮合酶和可溶性鸟苷酸环化酶刺激 cGMP 合成。 CD36配体阻断肉豆蔻酸刺激的cGMP积累与其抑制肉豆蔻酸吸收的能力成比例。 TSP1 还通过与其受体 CD47 结合来抑制肉豆蔻酸刺激的 cGMP 合成。肉豆蔻酸通过 NO/cGMP 途径刺激内皮和血管平滑肌细胞粘附在 I 型胶原上，而抑制肉豆蔻酸摄取的 CD36 配体则阻断了这种反应。因此，CD36 的脂肪酸转位酶活性在血管细胞中引发促血管生成信号传导，而 TSP1 通过同时抑制通过 CD36 的脂肪酸摄取和通过 CD47 的下游 cGMP 信号传导来抑制这种反应。
Although CD36 is generally recognized to be an inhibitory signaling receptor for thrombospondin- 1 (TSP1), the molecular mechanism for transduction of this signal remains unclear. Based on evidence that myristic acid and TSP1 each modulate endothelial cell nitric oxide signaling in a CD36-dependent manner, we examined the ability of TSP1 to modulate the fatty acid translocase activity of CD36. TSP1 and a CD36 antibody that mimics the activity of TSP1 inhibited myristate uptake. Recombinant TSP1 type 1 repeats were weakly inhibitory, but an anti-angiogenic peptide derived from this domain potently inhibited myristate uptake. This peptide also inhibited membrane translocation of the myristoylated CD36 signaling target Fyn and activation of Src family kinases. Myristate uptake stimulated cGMP synthesis via endothelial nitric-oxide synthase and soluble guanylyl cyclase. CD36 ligands blocked myristate-stimulated cGMP accumulation in proportion to their ability to inhibit myristate uptake. TSP1 also inhibited myristate-stimulated cGMP synthesis by engaging its receptor CD47. Myristate stimulated endothelial and vascular smooth muscle cell adhesion on type I collagen via the NO/cGMP pathway, and CD36 ligands that inhibit myristate uptake blocked this response. Therefore, the fatty acid translocase activity of CD36 elicits pro-angiogenic signaling in vascular cells, and TSP1 inhibits this response by simultaneously inhibiting fatty acid uptake via CD36 and downstream cGMP signaling via CD47.