Gaspar Renato Simões, Sage Tanya, Little Gemma, Kriek Neline, Pula Giordano, Gibbins Jonathan M
Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading RG6 6AH, UK.
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Eppendorf Hamburg, D-20246 Hamburg, Germany.
Antioxidants (Basel). 2021 Mar 23;10(3):497. doi: 10.3390/antiox10030497.
Protein disulphide isomerase (PDI) and NADPH oxidase 1 (Nox-1) regulate platelet function and reactive oxygen species (ROS) generation, suggesting potentially interdependent roles. Increased platelet reactivity and ROS production have been correlated with cardiometabolic disease risk factors.
To establish whether PDI and Nox-1 cooperate to control platelet function.
Immunofluorescence microscopy was utilised to determine expression and localisation of PDI and Nox-1. Platelet aggregation, fibrinogen binding, P-selectin exposure, spreading and calcium mobilization were measured as markers of platelet function. A cross-sectional population study ( = 136) was conducted to assess the relationship between platelet PDI and Nox-1 levels and cardiometabolic risk factors.
PDI and Nox-1 co-localized upon activation induced by the collagen receptor GPVI. Co-inhibition of PDI and Nox-1 led to additive inhibition of GPVI-mediated platelet aggregation, activation and calcium flux. This was confirmed in murine Nox-1 platelets treated with PDI inhibitor bepristat, without affecting bleeding. PDI and Nox-1 together contributed to GPVI signalling that involved the phosphorylation of p38 MAPK, p47phox, PKC and Akt. Platelet PDI and Nox-1 levels were upregulated in obesity, with platelet Nox-1 also elevated in hypertensive individuals.
We show that PDI and Nox-1 cooperate to control platelet function and are associated with cardiometabolic risk factors.
蛋白质二硫键异构酶（PDI）和NADPH氧化酶1（Nox-1）调节血小板功能和活性氧（ROS）生成，提示它们可能具有相互依存的作用。血小板反应性增加和ROS生成与心脏代谢疾病风险因素相关。
确定PDI和Nox-1是否协同控制血小板功能。
利用免疫荧光显微镜确定PDI和Nox-1的表达和定位。测量血小板聚集、纤维蛋白原结合、P-选择素暴露、铺展和钙动员，作为血小板功能的标志物。进行了一项横断面人群研究（n = 136），以评估血小板PDI和Nox-1水平与心脏代谢风险因素之间的关系。
在胶原受体GPVI诱导的激活后，PDI和Nox-1共定位。对PDI和Nox-一起抑制导致对GPVI介导的血小板聚集、激活和钙通量的叠加抑制。在用PDI抑制剂贝普利司他处理的小鼠Nox-1血小板中得到证实，且不影响出血。PDI和Nox-1共同促成了涉及p38 MAPK、p47phox、PKC和Akt磷酸化的GPVI信号传导。肥胖患者血小板中的PDI和Nox-1水平上调，高血压患者血小板中的Nox-1也升高。
我们表明，PDI和Nox-1协同控制血小板功能，并与心脏代谢风险因素相关。
