Kim Hyun Jung, Kim Kwang Seok, Kim Si Hyung, Baek Suk-Hwan, Kim Hwa Young, Lee ChuHee, Kim Jae-Ryong
Department of Biochemistry and Molecular Biology, Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, 317-1 Daemyung-Dong, Daegu 705-717, Republic of Korea.
J Gerontol A Biol Sci Med Sci. 2009 Mar;64(3):351-62. doi: 10.1093/gerona/gln055. Epub 2009 Mar 4.
Secretory phospholipase A(2) (sPLA(2)) is involved in various cellular physiological and pathological responses, especially in inflammatory responses. Accumulating evidence suggests that inflammation is an underlying basis for the molecular alterations that link aging and age-related pathological processes. However, the involvement of sPLA(2) in cellular senescence is not clear. In this study, we found that sPLA(2) treatment induces cellular senescence in human dermal fibroblasts (HDFs), as confirmed by increases in senescence-associated beta-galactosidase activity, changes in cell morphology, and upregulation of p53/p21 protein levels. sPLA(2)-induced senescence was observed in p16-knockdown HDFs and p16-null mouse fibroblasts, but not in p53-knockdown HDFs and p53-null mouse fibroblasts. Treatment with sPLA(2) increases reactive oxygen species (ROS) production, and an antioxidant, N-acetylcysteine, inhibits sPLA(2)-induced cellular senescence. These results suggest that sPLA(2) has a role in cellular senescence in HDFs during inflammatory response by promoting ROS-dependent p53 activation and might therefore contribute to inflammatory disorders associated with aging.
分泌型磷脂酶A2（sPLA(2)）参与多种细胞生理和病理反应，尤其是炎症反应。越来越多的证据表明，炎症是连接衰老和年龄相关病理过程的分子改变的潜在基础。然而，sPLA(2)在细胞衰老中的作用尚不清楚。在本研究中，我们发现sPLA(2)处理可诱导人皮肤成纤维细胞（HDFs）衰老，衰老相关β-半乳糖苷酶活性增加、细胞形态改变以及p53/p21蛋白水平上调均证实了这一点。在p16基因敲低的HDFs和p16基因缺失的小鼠成纤维细胞中观察到了sPLA(2)诱导的衰老，但在p53基因敲低的HDFs和p53基因缺失的小鼠成纤维细胞中未观察到。sPLA(2)处理可增加活性氧（ROS）的产生，而抗氧化剂N-乙酰半胱氨酸可抑制sPLA(2)诱导的细胞衰老。这些结果表明，sPLA(2)在炎症反应期间通过促进ROS依赖的p53激活在HDFs细胞衰老中起作用，因此可能导致与衰老相关的炎症性疾病。
