p38基因激活蛋白激酶降低了内皮前代细胞的调节
Florian H Seeger1, Judith Haendeler, Dirk H Walter
1Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Theodor-Stern-Kai 7, Frankfurt, Germany.
Circulation
|March 9, 2005
概括
通过葡萄糖和TNF-alpha激活MAP激酶会减少内皮原生细胞 (EPC) 数量. 用SB203580抑制p38激酶会增加EPC并改善新血管化,为细胞疗法提供了潜在的可能性.
科学领域:
- 心血管生物学 心血管生物学
- 细胞信号传递 细胞信号传递
- 再生医学是一种再生医学.
背景情况:
- 内皮原生细胞 (EPC) 对于新血管化至关重要,但在患有冠状动脉疾病 (CAD) 或糖尿病的患者中,其减少和功能受损.
- 研究像葡萄糖和TNF-α这样的危险因素对EPCs的影响对于理解这些损伤至关重要.
研究的目的:
- 阐明葡萄糖和TNF-alpha影响EPC数量和功能的机制.
- 确定p38 MAP 激酶信号在调节EPCs中的作用.
主要方法:
- 从健康受试者和CAD患者中分离出来的EPC.
- 用不同度的葡萄糖和TNF-alpha治疗的EPC.
- 分析了p38 MAP激酶通路的激活 (p38,MSK1,CREB的酸化).
- 使用了p38激酶抑制剂 (SB203580) 和主导阴性p38腺病毒.
- 评估EPC数,细胞亡,增殖,分化标志物 (CD14,CD64) 和体内新血管化能力.
主要成果:
- 葡萄糖和TNF-α剂量依赖性降低了EPC数量,而没有诱导亡.
- 这两种因素都激活了p38 MAP激酶通路,包括下游激酶和转录因子.
- 患有CAD的患者表现出较高的基底p38酸化.
- 抑制p38激酶显著增加了EPC数量和扩散.
- 在体内,SB203580治疗在CAD患者衍生的EPC中部分恢复了新血管化能力.
- 增加的EPC与减少的单细胞标志物表达相关,表明差异化发生了变化.
结论:
- p38 MAP 激酶是EPC数量和功能的关键调节者.
- 抑制p38激酶可以抵消葡萄糖和TNF-α对EPCs的有害影响.
- SB203580有可能改善心血管疾病中基于细胞的治疗方法的EPC数量.
相关概念视频
Negative Regulator Molecules
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
DNA Damage can Stall the Cell Cycle
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
Cell Specific Gene Expression
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...


