Dissociation of Pentameric to Monomeric C-Reactive Protein on Activated Platelets Localizes Inflammation to Atherosclerotic Plaques
Dissociation of Pentameric to Monomeric C-Reactive Protein on Activated Platelets Localizes Inflammation to Atherosclerotic Plaques
复制标题
DOI：
10.1161/circresaha.108.190611
复制
发表时间：
2009-07-17
影响因子：
20.1
通讯作者：
Peter, Karlheinz
中科院分区：
文献类型：
--
作者：
Eisenhardt, Steffen U.;Habersberger, Jonathon;Peter, Karlheinz
c反应蛋白（CRP）是心血管风险的预测因子。它作为五聚体（五聚体CRP）在血浆中循环。体内存在单体(m)CRP已被假设，但其功能和来源尚不清楚。我们发现mCRP沉积在人类主动脉和颈动脉粥样硬化斑块中，而不是在健康血管中。pCRP在健康血管和病变血管中均未发现。作为mCRP的来源，我们确定了pCRP解离到mCRP的机制。我们报道，活化血小板在心血管事件中发挥核心作用，通过溶血磷脂酰胆碱介导这种解离，溶血磷脂酰胆碱存在于活化而非静止的血小板上。此外，凋亡的单核细胞THP-1和Jurkat T细胞也可以介导pCRP向mCRP的解离。功能结果是揭示了实验环境中与动脉粥样硬化相关的病理生理学中CRP的促炎作用：与pCRP相比，mCRP诱导单核细胞趋化性增强；单核细胞活化，由整合素Mac-1的构象变化决定；活性氧的生成；静态和生理流动条件下单核细胞黏附。总之，我们证明了mCRP是通过pCRP在活化的血小板和h2o2处理的凋亡的THP-1和Jurkat T细胞上解离产生的，从而确定了CRP的促炎特性的局部揭开机制。这一新机制提供了已建立的心血管危险标志物、循环pCRP和局部血小板介导的炎症和致动脉粥样硬化作用之间的潜在联系。（Circ Res. 2009;105:128-137）
C-reactive protein (CRP) is a predictor of cardiovascular risk. It circulates as a pentamer (pentameric CRP) in plasma. The in vivo existence of monomeric (m)CRP has been postulated, but its function and source are not clear. We show that mCRP is deposited in human aortic and carotid atherosclerotic plaques but not in healthy vessels. pCRP is found neither in healthy nor in diseased vessels. As source of mCRP, we identify a mechanism of dissociation of pCRP to mCRP. We report that activated platelets, which play a central role in cardiovascular events, mediate this dissociation via lysophosphatidylcholine, which is present on activated but not resting platelets. Furthermore, the dissociation of pCRP to mCRP can also be mediated by apoptotic monocytic THP-1 and Jurkat T cells. The functional consequence is the unmasking of proinflammatory effects of CRP as demonstrated in experimental settings that are pathophysiologically relevant for atherogenesis: compared to pCRP, mCRP induces enhanced monocyte chemotaxis; monocyte activation, as determined by conformational change of integrin Mac-1; generation of reactive oxygen species; and monocyte adhesion under static and physiological flow conditions. In conclusion, we demonstrate mCRP generation via pCRP dissociation on activated platelets and H2O2-treated apoptotic THP-1 and Jurkat T cells, thereby identifying a mechanism of localized unmasking of the proinflammatory properties of CRP. This novel mechanism provides a potential link between the established cardiovascular risk marker, circulating pCRP, and localized platelet-mediated inflammatory and proatherogenic effects. (Circ Res. 2009;105:128-137.)