期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 292, 期 2, 页码 C850-C856出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00356.2006
关键词
diabetes; connective tissue; mitogen-activated protein kinase; reactive oxygen species
资金
- NIAMS NIH HHS [P01 AR-49920] Funding Source: Medline
- NIDCR NIH HHS [R01 DE-07559, R01 DE-14066, R01 DE007559] Funding Source: Medline
Advanced glycation end products ( AGEs) are elevated in aged and diabetic individuals and are associated with pathological changes associated with both. Previously we demonstrated that the AGE N-epsilon-( carboxymethyl) lysine ( CML)- collagen induced fibroblast apoptosis through the cytoplasmic and mitochondrial pathways and the global induction of proapoptotic genes. In the present study we investigated upstream mechanisms of CML- collagen- induced apoptosis. CML- collagen induced activation of the proapoptotic transcription factor FOXO1 compared with unmodified collagen. When FOXO1 was silenced, CML- collagen- stimulated apoptosis was reduced by similar to 75% compared with fibroblasts incubated with nonsilencing small interfering RNA, demonstrating the functional significance of FOXO1 activation ( P < 0.05). CML- collagen but not control collagen also induced a 3.3- fold increase in p38 and a 5.6- fold increase in JNK( 1/ 2) activity ( P < 0.05). With the use of specific inhibitors, activation of p38 and JNK was shown to play an important role in CML- collagen- induced activation of FOXO1 and caspase- 3. Moreover, inhibition of p38 and JNK reduced CML- collagen- stimulated apoptosis by 48 and 57%, respectively, and by 89% when used together ( P < 0.05). In contrast, inhibition of the phosphatidylinositol 3- kinase/ Akt pathway enhanced FOXO1 activation. p38 and JNK stimulation by CML- collagen was almost entirely blocked when formation of ROS was inhibited and was partially reduced by NO and ceramide inhibitors. These inhibitors also reduced apoptosis to a similar extent. Together these data support a model in which AGE- induced apoptosis involves the formation of ROS, NO, and ceramide and leads to p38 and JNK MAP kinase activation, which in turn induces FOXO1 and caspase- 3.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据