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首页> 外文期刊>Journal of Cellular Physiology >Engineered endothelial progenitor cells that overexpress prostacyclin protect vascular cells
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Engineered endothelial progenitor cells that overexpress prostacyclin protect vascular cells

机译：工程内皮祖细胞保护血管内皮细胞过表达

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摘要

Prostacyclin (PGI2) is a potent vasodilator and important mediator of vascular homeostasis; however, its clinical use is limited because of its short (2-min) half-life. Thus, we hypothesize that the use of engineered endothelial progenitor cells (EPCs) that constitutively secrete high levels of PGI2 may overcome this limitation of PGI2 therapy. A cDNA encoding COX-1-10aa-PGIS, which links human cyclooxygenase-1 (COX-1) to prostacyclin synthase (PGIS), was delivered via nucleofection into outgrowth EPCs derived from rat bone marrow mononuclear cells. PGI2-secreting strains (PGI2-EPCs) were established by continuous subculturing of transfected cells under G418 selection. Genomic PCR, RT-PCR, and Western blot analyses confirmed the overexpression of COX-1-10aa-PGIS in PGI2-EPCs. PGI2-EPCs secreted significantly higher levels of PGI2 in vitro than native EPCs (P0.05) and showed higher intrinsic angiogenic capability; conditioned medium (CM) from PGI2-EPCs promoted better tube formation than CM from native EPCs (P0.05). Cell- and paracrine-mediated in vitro angiogenesis was attenuated when COX-1-10aa-PGIS protein expression was knocked down. Whole-cell patch-clamp studies showed that 4-aminopyridine-sensitive K + current density was increased significantly in rat smooth muscle cells (rSMCs) cocultured under hypoxia with PGI2-EPCs (7.50±1.59pA/pF; P0.05) compared with rSMCs cocultured with native EPCs (3.99±1.26pA/pF). In conclusion, we successfully created EPC strains that overexpress an active novel enzyme resulting in consistent secretion of PGI2. PGI2-EPCs showed enhanced intrinsic proangiogenic properties and provided favorable paracrine-mediated cellular protections, including promoting in vitro angiogenesis of native EPCs and hyperpolarization of SMCs under hypoxia.
机译：环前列腺素(PGI2)是一种强有力的血管舒张血管内稳态的重要中介;然而,其临床使用是有限的,因为半衰期短(& 2分钟)。假设工程的使用内皮祖细胞(epc)持续分泌PGI2水平高的可能克服这种限制PGI2疗法。编码COX-1-10aa-PGIS,联系着人类cyclooxygenase-1环前列腺素合成酶(COX-1)(PGIS),都是经由nucleofection从大鼠骨髓内皮祖细胞产物衍生单核细胞。(PGI2-EPCs)是由连续的转染细胞的接种G418之下选择。分析证实了超表达的COX-1-10aa-PGIS PGI2-EPCs。体外PGI2水平显著高于本机epc(术中;0.05)和显示更高内在血管生成能力;介质(CM)从PGI2-EPCs提升更好的管形成比厘米从本地epc(术中,0.05)。细胞和paracrine-mediated体外血管生成是COX-1-10aa-PGIS时减弱蛋白表达是撞倒了。膜片钳研究表明,4-aminopyridine-sensitive K +电流密度在大鼠平滑肌显著增加细胞(rSMCs) cocultured下缺氧PGI2-EPCs(7.50±1.59 pa / pF;与rSMCs cocultured与本机内皮祖细胞(3.99±1.26 pa / pF)。创建EPC菌株中的一个活跃的过表达小说的分泌酶导致一致的PGI2。proangiogenic属性和提供有利的paracrine-mediated细胞保护,包括促进体外血管生成本机epc和超极化下的smc缺氧。

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