Thrombospondin-1-CD47 blockade and exogenous nitrite enhance ischemic tissue survival, blood flow and angiogenesis via coupled NO-cGMP pathway activation.
Thrombospondin-1-CD47 blockade and exogenous nitrite enhance ischemic tissue survival, blood flow and angiogenesis via coupled NO-cGMP pathway activation.
复制标题
DOI：
10.1016/j.niox.2009.05.005
复制
发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
Gladwin M
中科院分区：
文献类型：
--
作者：
Isenberg JS;Shiva S;Gladwin M
组织缺血和缺血再灌注（I/R）仍然是细胞和组织死亡的来源。无法恢复血流和限制再灌注损伤是外科组织修复和移植的一个挑战。一氧化氮（NO）是血流、再灌注信号和血管生成的中心调节因子。从头合成一氧化氮需要氧气，并且在缺血血管区域受到限制。亚硝酸盐（NO2-）已被发现在缺氧时通过血红素还原转化为NO，提供了一个不依赖于NO合成酶和氧的NO来源。此外，基质蛋白血栓反应蛋白-1 （TSP1）或其受体CD47的阻断已被证明可通过可溶性鸟苷酸环化酶（sGC）和cgmp依赖性激酶促进下游NO信号传导。我们假设亚硝酸盐提供了一种缺血NO来源，可以通过TSP1-CD47阻断增强缺血组织存活、血流和血管生成。低剂量亚硝酸盐和使用抗体或基因沉默直接阻断TSP1-CD47相互作用均可增加缺血全层皮瓣的急性血流量和晚期组织存活。亚硝酸盐和TSP-1阻断均增强了体外和体内血管生成反应。亚硝酸盐效应可以通过抑制sGC和cGMP信号通路来消除。在更严重的缺血皮瓣模型中测试了潜在的治疗协同作用。我们发现亚硝酸盐和TSP1-CD47阻断联合治疗比单独使用任何一种药物更能增强皮瓣的灌注、存活和血管生成，提供约100%的皮瓣存活率。这些数据为缺氧NO信号通过TSP1-CD47阻断和亚硝酸盐递送介导的cGMP增强提供了新的治疗范式。
Tissue ischemia and ischemia-reperfusion (I/R) remain sources of cell and tissue death. Inability to restore blood flow and limit reperfusion injury represents a challenge in surgical tissue repair and transplantation. A central regulator of blood flow, reperfusion signaling and angiogenesis is nitric oxide (NO). De novo NO synthesis requires oxygen and is limited in ischemic vascular territories. Nitrite (NO2-) has been discovered to convert to NO via heme-based reduction during hypoxia, providing a NO synthase independent and oxygen-independent NO source. Furthermore, blockade of the matrix protein thrombospondin-1 (TSP1) or its receptor CD47 has been shown to promote down-stream NO signaling via soluble guanylate cyclase (sGC) and cGMP-dependant kinase. We hypothesized nitrite would provide an ischemic NO source that could be potentiated by TSP1-CD47 blockade enhancing ischemic tissue survival, blood flow and angiogenesis. Both low dose nitrite and direct blockade of TSP1-CD47 interaction using antibodies or gene silencing increased acute blood flow and late tissue survival in ischemic full thickness flaps. Nitrite and TSP-1 blockade both enhanced in vitro and in vivo angiogenic responses. The nitrite effect could be abolished by inhibition of sGC and cGMP signaling. Potential therapeutic synergy was tested in a more severe ischemic flap model. We found that combined therapy with nitrite and TSP1-CD47 blockade enhanced flap perfusion, survival and angiogenesis to a greater extent than either agent alone, providing approximately 100% flap survival. These data provide a new therapeutic paradigm for hypoxic NO signaling through enhanced cGMP mediated by TSP1-CD47 blockade and nitrite delivery.
登录
查看更多内容
影响因子：
20.1
作者：
Isenberg, Jeff S.;Romeo, Martin J.;Roberts, David D.
通讯作者：
Roberts, David D.
影响因子：
9
作者：
Isenberg, Jeff S.;Pappan, Loretta K.;Roberts, David D.
通讯作者：
Roberts, David D.
影响因子：
2.2
作者：
Amadeu, Thais P.;Seabra, Amedea. B.;Monte-Alto-Costa, Andrea
通讯作者：
Monte-Alto-Costa, Andrea
影响因子：
2.1
作者：
KERRIGAN, CL;STOTLAND, MA
通讯作者：
STOTLAND, MA
影响因子：
6
作者：
KNIGHT, KR;ANGEL, MF;OBRIEN, BM
通讯作者：
OBRIEN, BM