Scharner Dörte, Rössig Lothar, Carmona Guillaume, Chavakis Emmanouil, Urbich Carmen, Fischer Ariane, Kang Tae-Bong, Wallach David, Chiang Yungping Jeffrey, Deribe Yonathan Lissanu, Dikic Ivan, Zeiher Andreas M, Dimmeler Stefanie
Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany.
Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):571-8. doi: 10.1161/ATVBAHA.108.182006. Epub 2009 Jan 2.
Endothelial progenitor cells (EPCs) comprise a heterogeneous population of cells, which improve therapeutic neovascularization after ischemia. The neovascularization-promoting potential of progenitor cells depends on survival and retention of the infused cells to the tissue. Caspases mediate apoptosis but are also involved in other critical biological processes. Therefore, we aimed to address the role of caspases in proangiogenic cells.
The caspase-8 inhibitor zIETD abrogated the ex vivo formation of EPCs, inhibited EPC adhesion and migration, and reduced their capacity to improve neovascularization in vivo. Consistently, cells isolated from caspase-8-deficient mice exhibited a reduced capacity for enhancing neovascularization when transplanted into mice after hindlimb ischemia. Because inhibition of Caspase-8 reduced the adhesion and homing functions of EPCs, we further determined the surface expression of integrins and receptors involved in cell recruitment to ischemic tissues. Pharmacological inhibition of caspase-8 and genetic depletion of caspase-8 reduced the expression of the fibronectin receptor subunits alpha5 and beta1 and the SDF-1 receptor CXCR4. Moreover, we identified the E3 ubiquitin ligase Cbl-b, which negatively regulates integrin and receptor-mediated signaling, as a potential Caspase-8 substrate.
In summary, our data demonstrate a novel apoptosis-unrelated role of caspase-8 in proangiogenic cells.
内皮祖细胞（EPCs）是一类异质性细胞群体，可改善缺血后的治疗性血管新生。祖细胞促进血管新生的潜能取决于注入细胞在组织中的存活和留存。半胱天冬酶介导细胞凋亡，但也参与其他关键生物学过程。因此，我们旨在探讨半胱天冬酶在促血管生成细胞中的作用。
半胱天冬酶-8抑制剂zIETD消除了EPCs的体外形成，抑制了EPCs的黏附与迁移，并降低了它们在体内改善血管新生的能力。同样，从半胱天冬酶-8缺陷小鼠分离的细胞在移植到后肢缺血小鼠体内后，增强血管新生的能力降低。由于抑制半胱天冬酶-8降低了EPCs的黏附与归巢功能，我们进一步测定了参与细胞募集至缺血组织的整合素和受体的表面表达。半胱天冬酶-8的药理学抑制和基因敲除降低了纤连蛋白受体亚基α5和β1以及SDF-1受体CXCR4的表达。此外，我们鉴定出E3泛素连接酶Cbl-b作为潜在的半胱天冬酶-8底物，其负向调节整合素和受体介导的信号传导。
总之，我们的数据证明了半胱天冬酶-8在促血管生成细胞中具有一种与凋亡无关的新作用。
