Kovanen Petri T
Wihuri Research Institute, Helsinki, Finland.
Immunol Rev. 2007 Jun;217:105-22. doi: 10.1111/j.1600-065X.2007.00515.x.
Our understanding of the relationship between the proatherogenic activities of arterial mast cells (MCs) and the development of atherosclerotic lesions is advancing. Atherosclerosis is a chronic inflammatory disease in which cholesterol and other lipids of circulating low-density lipoprotein (LDL) particles accumulate both extracellularly and intracellularly in the innermost layer of the arterial wall, the intima. One prerequisite for the proatherogenic activity of the LDL particles is their retention and proteolytic modification within the extracellular matrix of the intima. Experimental studies with activated chymase-secreting MCs have provided us fundamental insights into the molecular mechanisms of these processes. High-density lipoprotein (HDL) particles, again, remove cholesterol from the intracellular stores and carry it back to the circulation. MC chymase and tryptase actively degrade HDL and thus generate functionally defective particles that are unable to initiate cholesterol efflux from the arterial wall. In advanced atherosclerotic plaques, the accumulated lipids are separated from the circulation by a collagenous cap. By inducing apoptosis of endothelial cells (ECs), subendothelial MCs may induce detachment of ECs from the cap (plaque erosion). Moreover, MCs may weaken the cap if they disturb local collagen turnover by inducing apoptosis of the collagen-secreting smooth muscle cells or when they promote collagen degradation by activating matrix metalloproteinases. Plaques with a weak cap are vulnerable to rupture. The exposed subendothelial tissue at eroded and ruptured sites of plaques triggers local development of a platelet-rich thrombus. As regulators of the collagen-induced platelet activation and fibrin formation/fibrinolysis, the MCs may retard or accelerate the growth of the plaque-associated thrombus and ultimately participate in the wound-healing response of the injured plaque. We propose that by promoting cholesterol accumulation and plaque vulnerability and by locally regulating hemostasis, MCs in atherosclerotic lesions have the potential to contribute to the clinical outcomes of atherosclerosis, such as myocardial infarction and stroke.
我们对动脉肥大细胞（MCs）的促动脉粥样硬化活性与动脉粥样硬化病变发展之间关系的理解正在不断深入。动脉粥样硬化是一种慢性炎症性疾病，其中循环中的低密度脂蛋白（LDL）颗粒中的胆固醇和其他脂质在动脉壁最内层即内膜的细胞外和细胞内积聚。LDL颗粒促动脉粥样硬化活性的一个先决条件是它们在内膜细胞外基质中的滞留和蛋白水解修饰。对分泌糜酶的活化MCs进行的实验研究为我们提供了对这些过程分子机制的基本认识。高密度脂蛋白（HDL）颗粒则从细胞内储存中清除胆固醇并将其带回循环。MC糜酶和类胰蛋白酶会积极降解HDL，从而产生功能有缺陷的颗粒，这些颗粒无法启动胆固醇从动脉壁的流出。在晚期动脉粥样硬化斑块中，积聚的脂质被一层胶原帽与循环隔离开来。通过诱导内皮细胞（ECs）凋亡，内膜下MCs可能会诱导ECs从帽上脱落（斑块侵蚀）。此外，如果MCs通过诱导分泌胶原蛋白的平滑肌细胞凋亡干扰局部胶原蛋白周转，或者通过激活基质金属蛋白酶促进胶原蛋白降解，它们可能会削弱帽的强度。帽薄弱的斑块容易破裂。斑块侵蚀和破裂部位暴露的内膜下组织会引发富含血小板血栓的局部形成。作为胶原蛋白诱导的血小板活化和纤维蛋白形成/纤维蛋白溶解的调节因子，MCs可能会延缓或加速斑块相关血栓的生长，并最终参与受损斑块的伤口愈合反应。我们提出，通过促进胆固醇积聚和斑块易损性以及局部调节止血，动脉粥样硬化病变中的MCs有可能影响动脉粥样硬化的临床结局，如心肌梗死和中风。
