Regulation of smooth muscle cell growth, function and death in vitro by activated mast cells - a potential mechanism for the weakening and rupture of atherosclerotic plaques
Regulation of smooth muscle cell growth, function and death in vitro by activated mast cells - a potential mechanism for the weakening and rupture of atherosclerotic plaques
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DOI：
10.1016/s0006-2952(03)00503-3
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发表时间：
2003-10-15
影响因子：
5.8
通讯作者：
Lindstedt, KA
中科院分区：
文献类型：
--
作者：
Leskinen, MJ;Kovanen, PT;Lindstedt, KA
含脂质的动脉粥样硬化斑块的纤维帽由合成表型的动脉平滑肌细胞（SMC）产生的胶原组成。厚的帽保护富含脂质的核心，而薄的帽使其容易破裂，随之而来的是急性临床并发症，如心肌梗死。在导致斑块弱化和破裂的病理机制中，一种可能性是基质合成SMC的丧失。事实上，冠状动脉斑块破裂的冠状动脉帽含有数量减少的SMC。相反。在这样的损伤中。活化的炎性细胞如肥大细胞的数量增加，表明它们可以调节SMC的数量。我们已经证明，由活化的肥大细胞分泌的肝素蛋白聚糖可以有效地抑制SMC在体外的增殖，并降低其产生胶原的能力。糜酶是一种由活化的肥大细胞分泌的中性丝氨酸蛋白酶，也可以通过转化生长因子-P依赖性和非依赖性机制抑制SMC介导的胶原合成，此外，通过激活潜伏的间质胶原酶（MMP-1）引起胶原基质的降解。此外，糜酶可以通过降解SMC粘附所需的细胞外基质成分纤连蛋白来诱导SMC凋亡，随后破坏局灶性粘附并失去由外向内的生存信号传导。因此，活化的肥大细胞可能通过分泌影响动脉SMC生长、功能和死亡的介质，如肝素蛋白聚糖和糜酶，参与动脉粥样硬化斑块的弱化和破裂。(C)2003年爱思唯尔公司All rights reserved.
The fibrous cap of a lipid-containing atherosclerotic plaque consists of collagen produced by arterial smooth muscle cells (SMCs) of synthetic phenotype. A thick cap protects the lipid-rich core, whereas a thin cap predisposes it to rupture, with ensuing acute clinical complications, such as myocardial infarction. Among the pathological mechanisms leading to plaque weakening and rupture, one possibility is loss of the matrix-synthesizing SMCs. Indeed, caps of ruptured coronary plaques contain a reduced number of SMCs. In contrast. in such lesions. the number of activated inflammatory cells, such as mast cells, is increased, suggesting that they may regulate the SMC number. We have shown that heparin proteoglycans secreted by activated mast cells can efficiently inhibit proliferation of SMCs in vitro and reduce their ability to produce collagen. Chymase, a neutral serine protease secreted by activated mast cells, can also inhibit SMC-mediated collagen synthesis by a transforming growth factor-P-dependent and -independent mechanism, and moreover, cause degradation of the collagen matrix by activating latent interstitial collagenase (MMP-1). Furthermore, chymase can induce SMC apoptosis by degrading the extracellular matrix component fibronectin necessary for SMC adhesion, with subsequent disruption of focal adhesions and loss of outside-in survival signaling. Thus, activated mast cells may participate in the weakening and rupture of atherosclerotic plaques by secreting mediators, such as heparin proteoglycans and chymase, which affect the growth, function and death of arterial SMCs. (C) 2003 Elsevier Inc. All rights reserved.