Mitochondrial calcium and reactive oxygen species regulate agonist-initiated platelet phosphatidylserine exposure.
Mitochondrial calcium and reactive oxygen species regulate agonist-initiated platelet phosphatidylserine exposure.
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DOI：
10.1161/atvbaha.112.300433
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Jobe SM
中科院分区：
文献类型：
--
作者：
Choo HJ;Saafir TB;Mkumba L;Wagner MB;Jobe SM
目的：研究细胞内钙离子(Ca~(2+))升高、线粒体通透性转换孔(MPTP)形成和活性氧(ROS)形成在调节血小板磷脂酰丝氨酸(PS)暴露中的相互作用。在野生型、CypD缺失、离子霉素处理和ROS处理的血小板中，MPTP的形成与PS暴露有关，而与Ca2+细胞升高的程度无关。在没有MPTP调节剂的情况下，亲环素D激动剂启动的MPTP形成和高水平PS暴露明显钝化，但Ca~(2+)细胞瞬变不变。在强烈刺激的血小板中，检测了线粒体钙(Ca~(2+))瞬变和ROS，它们是MPTP形成的关键调节因素。ROS产生的增加发生在强烈刺激的血小板上，并且依赖于细胞外钙内流，而不是CypD的存在。在强烈刺激的血小板中，Ca2+MIT显著增加。通过抑制线粒体钙单转运体或线粒体去极化来阻止钙离子进入，可阻止MPTP的形成和暴露，但不能阻止血小板聚集或颗粒释放。持续的钙离子细胞水平对于高水平的PS反应激动剂是必要的，但不是充分的。钙离子MIT水平升高是启动MPTP形成和PS暴露的关键信号。阻断Ca~(2+)-MIT进入可以特异性地抑制血小板的促凝活性。
To study the interactions of cytoplasmic calcium (Ca2+cyt) elevation, mitochondrial permeability transition pore (mPTP) formation, and reactive oxygen species (ROS) formation in the regulation of phosphatidylserine (PS) exposure in platelets. mPTP formation, but not the degree of Ca2+cyt elevation, was associated with PS exposure in wild-type, CypD null, ionomycin-treated and ROS-treated platelets. In the absence of the mPTP regulator cyclophilin D agonist-initiated mPTP formation and high-level PS exposure were markedly blunted, but Ca2+cyt transients were unchanged. Mitochondrial calcium (Ca2+mit) transients and ROS, key regulators of mPTP formation, were examined in strongly-stimulated platelets. Increased ROS production occurred in strongly-stimulated platelets and was dependent on extracellular calcium entry, but not the presence of CypD. Ca2+mit increased significantly in strongly-stimulated platelets. Abrogation of Ca2+mit entry either by inhibition of the mitochondrial calcium uniporter or mitochondrial depolarization prevented mPTP formation and exposure, but not platelet aggregation or granule release. Sustained Ca2+cyt levels are necessary, but not sufficient, for high-level PS exposure in response to agonists. Increased Ca2+mit levels are a key signal initiating mPTP formation and PS exposure. Blockade of Ca2+mit entry allows the specific inhibition of platelet procoagulant activity.