Kruppel-like Factor 5 Shows Proliferation-specific Roles in Vascular Remodeling, Direct Stimulation of Cell Growth, and Inhibition of Apoptosis
Kruppel-like Factor 5 Shows Proliferation-specific Roles in Vascular Remodeling, Direct Stimulation of Cell Growth, and Inhibition of Apoptosis
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DOI：
10.1074/jbc.m806230200
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发表时间：
2009-04-03
影响因子：
4.8
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Suzuki, Toru;Sawaki, Daigo;Nagai, Ryozo
Kruppel样因子5（KLF 5）最初作为血管平滑肌细胞表型调节的调节因子分离，诱导病理性细胞生长并在新生内膜中表达。虽然KLF 5的诱导上调生长因子如血小板衍生生长因子-A链，但KLF 5实际上如何促进血管重塑，特别是其对细胞增殖的直接影响尚不清楚。为了研究KLF 5对新生内膜形成的影响，我们首先对颈动脉球囊损伤的大鼠进行腺病毒过表达KLF 5。损伤后14天，KLF 5治疗组的新生内膜形成和增殖细胞核抗原阳性率显著增加。在细胞水平上，KLF 5的过表达也导致细胞增殖和细胞周期进展的显著增加。作为一种分子机制，我们发现KLF 5直接结合到启动子和上调基因表达的细胞周期蛋白D1，以及显示特定的反式激活的细胞周期蛋白和细胞周期蛋白依赖性激酶抑制剂在心血管细胞。相反，通过RNA干扰敲低KLF 5特异性下调细胞周期蛋白D1并损害血管平滑肌细胞增殖。此外，KLF 5减弱了凋亡刺激条件下caspase-3的裂解。此外，KLF 5给药的动物表现出显着减少的末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性细胞在中层，这表明细胞凋亡的抑制在早期阶段后剥脱。这些研究结果共同表明，KLF 5通过直接和特异性刺激细胞生长以及抑制细胞凋亡在心血管病理学中发挥核心作用。
Kruppel-like factor 5 (KLF5), originally isolated as a regulator of phenotypic modulation of vascular smooth muscle cells, induces pathological cell growth and is expressed in the neointima. Although induction of KLF5 up-regulates growth factors like platelet derived growth factor-A chain, how KLF5 actually contributes to vascular remodeling, notably its direct effects on cell proliferation, had been poorly clarified. To investigate the effects of KLF5 on neointimal formation, we at first performed adenoviral overexpression of KLF5 to rats subjected to carotid balloon injury. Neointimal formation and proliferating cell nuclear antigen-positive rate were significantly increased at 14 days after injury in the KLF5-treated animals. At the cellular level, overexpression of KLF5 also resulted in markedly increased cell proliferation and cell cycle progression. As a molecular mechanism, we showed that KLF5 directly bound to the promoter and up-regulated gene expression of cyclin D1, as well as showing specific transactivation of cyclins and cyclin-dependent kinase inhibitors in cardiovascular cells. Conversely, knockdown of KLF5 by RNA interference specifically down-regulated cyclin D1 and impaired vascular smooth muscle cell proliferation. Furthermore, KLF5 attenuated cleavage of caspase-3 under conditions of apoptotic stimulation. Moreover, KLF5-administered animals exhibited a significant decrease in terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling positive cells in the medial layer, suggesting inhibition of apoptosis in the early phase after denudation. These findings collectively suggest that KLF5 plays a central role in cardiovascular pathologies through direct and specific stimulation of cell growth as well as inhibition of apoptosis.