Protein disulfide isomerase regulation by nitric oxide maintains vascular quiescence and controls thrombus formation.
Protein disulfide isomerase regulation by nitric oxide maintains vascular quiescence and controls thrombus formation.
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DOI：
10.1111/jth.14291
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Flaumenhaft R
中科院分区：
文献类型：
--
作者：
Bekendam RH;Iyu D;Passam F;Stopa JD;De Ceunynck K;Muse O;Bendapudi PK;Garnier CL;Gopal S;Crescence L;Chiu J;Furie B;Panicot-Dubois L;Hogg PJ;Dubois C;Flaumenhaft R
蛋白质二硫键异构酶（PDI）在血栓形成中起重要作用，PDI抑制剂作为一种新型抗凝剂正在临床上进行评价。然而，对血管中PDI的调节知之甚少。PDI的催化基序内的巯基对于其在血栓形成中的作用是必不可少的。这些相同的硫醇结合一氧化氮（NO），一种有效的血管功能调节剂。为了确定PDI的调节是否代表NO控制血管静止的机制，我们评估了NO对内皮细胞、血小板和体内血栓形成中PDI功能的影响。评估S-亚硝基化对血管系统中PDI和其他巯基异构酶调节的影响。内源性NO对PDI活性的作用进行了评估，通过孵育内皮细胞与NO清除剂，这导致暴露的游离巯基，巯基异构酶活性增加，并增强凝血酶生成的细胞膜上。相反，内皮细胞暴露于NO+载体或通过诱导NO合成升高内源性NO水平导致PDI的S-亚硝基化和表面巯基还原酶活性降低。血小板PDI的S-亚硝基化抑制其还原酶活性，S-亚硝基化的PDI干扰血小板聚集、α-颗粒释放和血小板上凝血酶的生成。S-亚硝基化的PDI在注入小鼠体内时也阻断了激光诱导的血栓形成。发现S-亚硝基化ERp 5和ERp 57具有相似的抑制活性。这些研究将NO确定为血管PDI的关键调节剂，并将PDI功能的调节定义为NO维持血管静止的重要机制。
Protein disulfide isomerase (PDI) serves an essential role in thrombus formation and PDI inhibition is being evaluated clinically as a novel anticoagulant. Yet little is known about the regulation of PDI in the vasculature. Thiols within the catalytic motif of PDI are essential for its role in thrombosis. These same thiols bind nitric oxide (NO), a potent regulator of vessel function. To determine whether regulation of PDI represents a mechanism by which NO controls vascular quiescence, we evaluated the effect of NO on PDI function in endothelial cells, platelets, and thrombus formation in vivo. To assess the effect of S-nitrosylation on the regulation of PDI and other thiol isomerases in the vasculature. The role of endogenous NO on PDI activity was evaluated by incubating endothelium with a NO scavenger, which resulted in exposure of free thiols, increased thiol isomerase activity, and enhanced thrombin generation on the cell membrane. Conversely, exposure of endothelium to NO+ carriers or elevation of endogenous NO levels by induction of NO synthesis resulted in S-nitrosylation of PDI and decreased surface thiol reductase activity. S-nitrosylation of platelet PDI inhibited its reductase activity and S-nitrosylated PDI interfered with platelet aggregation, α-granule release, and thrombin generation on platelets. S-nitrosylated PDI also blocked laser-induced thrombus formation when infused into mice. S-nitrosylated ERp5 and ERp57 were found to have similar inhibitory activity. These studies identify NO as a critical regulator of vascular PDI and define regulation of PDI function as an important mechanism by which NO maintains vascular quiescence.
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DOI：
10.1073/pnas.142136499
发表时间：
2002-07-09
影响因子：
11.1
作者：
Akhter, S;Vignini, A;Mutus, B
通讯作者：
Mutus, B
DOI：
10.1161/atvbaha.116.307461
发表时间：
2016-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Crescente M;Pluthero FG;Li L;Lo RW;Walsh TG;Schenk MP;Holbrook LM;Louriero S;Ali MS;Vaiyapuri S;Falet H;Jones IM;Poole AW;Kahr WH;Gibbins JM
通讯作者：
Gibbins JM
影响因子：
16.6
作者：
Bekendam, Roelof H.;Bendapudi, Pavan K.;Lin, Lin;Nag, Partha P.;Pu, Jun;Kennedy, Daniel R.;Feldenzer, Alexandra;Chiu, Joyce;Cook, Kristina M.;Furie, Bruce;Huang, Mingdong;Hogg, Philip J.;Flaumenhaft, Robert
通讯作者：
Flaumenhaft, Robert
DOI：
10.1152/ajpheart.00819.2004
发表时间：
2005-04-01
影响因子：
4.8
作者：
Iafrati, MD;Vitseva, O;Freedman, JE
通讯作者：
Freedman, JE
影响因子：
82.9
作者：
Falati, S;Gross, P;Furie, B
通讯作者：
Furie, B