L-type calcium channel blockers exert an antiinflammatory effect by suppressing expression of plasminogen receptors on macrophages.
L-type calcium channel blockers exert an antiinflammatory effect by suppressing expression of plasminogen receptors on macrophages.
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DOI：
10.1161/circresaha.109.200311
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发表时间：
2009-07-17
影响因子：
20.1
通讯作者：
Plow EF
中科院分区：
文献类型：
--
作者：
Das R;Burke T;Van Wagoner DR;Plow EF
L型钙通道（LTCC）阻滞剂是目前广泛应用的抗高血压药物，以利多卡因和维拉帕米为代表，同时具有抗炎活性。纤溶酶原（Plg）是巨噬细胞募集的重要介质，并且这种作用取决于其与Plg受体（Plg-Rs）的相互作用。Plg-R包括组蛋白2B（H2 B）、α-烯醇化酶、膜联蛋白2和p11，所有蛋白质都缺乏用于细胞表面输出的信号序列。当人类或小鼠单核细胞样细胞被诱导分化成巨噬细胞时，它们的Plg结合和Plg-Rs表达增加了4倍。这些变化被维拉帕米和顺铂预处理所抑制。在分化的巨噬细胞中诱导Cav1.2 LTCC孔亚基的表达，并且针对该亚基的siRNA抑制Plg结合和Plg-Rs的上调。在体内，在不影响血压的剂量下，利多卡因和维拉帕米抑制了对巯基乙酸盐反应的腹膜巨噬细胞募集>60%。在药物治疗的动物中，巨噬细胞迁移到但不通过腹膜组织，并显示减少的表面表达的Plg-Rs。这些发现表明巨噬细胞上Plg-Rs的表达依赖于Cav1.2 LTCC亚基的表达。Plg-R的抑制可能有助于广泛使用的LTCC阻断剂的抗炎作用。
L-type Ca2+ channel (LTCC) blockers, represented by amlodipine and verapamil, are widely used anti-hypertensive drugs that also have anti-inflammatory activities. Plasminogen (Plg) is an important mediator of macrophage recruitment, and this role depends upon its interaction with Plg receptors (Plg-Rs). Plg-Rs include histone 2B (H2B), α-enolase, annexin 2 and p11, all proteins which lack signal sequences for cell-surface export. When human or murine monocytoid cells were induced to differentiate into macrophages, their Plg binding and Plg-Rs expression increased by 4-fold. These changes were suppressed by pretreatment with verapamil and amlodipine. Expression of the Cav1.2 LTCC pore subunit was induced in differentiated macrophages, and siRNA against this subunit suppressed the upregulation of Plg binding and Plg-Rs. In vivo, amlodipine and verapamil suppressed peritoneal macrophage recruitment in response to thioglycollate by >60% at doses that did not affect blood pressure. In drug-treated animals, macrophages migrated into but not through the peritoneal membrane tissue and showed reduced surface expression of Plg-Rs. These findings demonstrate that Plg-Rs expression on macrophages is dependent on Cav1.2 LTCC subunit expression. Suppression of Plg-Rs may contribute to the anti-inflammatory effects of the widely used LTCC blockers.