Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors
Background: 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 fac...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-03-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/3/497 |
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| author | Renato Simões Gaspar Tanya Sage Gemma Little Neline Kriek Giordano Pula Jonathan M. Gibbins |
| author_facet | Renato Simões Gaspar Tanya Sage Gemma Little Neline Kriek Giordano Pula Jonathan M. Gibbins |
| author_sort | Renato Simões Gaspar |
| collection | DOAJ |
| description | Background: 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. Objectives: To establish whether PDI and Nox-1 cooperate to control platelet function. Methods: 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 (<i>n</i> = 136) was conducted to assess the relationship between platelet PDI and Nox-1 levels and cardiometabolic risk factors. Results: 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<sup>−/−</sup> 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. Conclusions: We show that PDI and Nox-1 cooperate to control platelet function and are associated with cardiometabolic risk factors. |
| first_indexed | 2024-03-10T12:58:58Z |
| format | Article |
| id | doaj.art-65daa46e53894e548f123dec15b19d9d |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T12:58:58Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-65daa46e53894e548f123dec15b19d9d2023-11-21T11:41:37ZengMDPI AGAntioxidants2076-39212021-03-0110349710.3390/antiox10030497Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk FactorsRenato Simões Gaspar0Tanya Sage1Gemma Little2Neline Kriek3Giordano Pula4Jonathan M. Gibbins5Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading RG6 6AH, UKInstitute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading RG6 6AH, UKInstitute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading RG6 6AH, UKInstitute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading RG6 6AH, UKInstitute for Clinical Chemistry and Laboratory Medicine, University Medical Center Eppendorf Hamburg, D-20246 Hamburg, GermanyInstitute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading RG6 6AH, UKBackground: 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. Objectives: To establish whether PDI and Nox-1 cooperate to control platelet function. Methods: 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 (<i>n</i> = 136) was conducted to assess the relationship between platelet PDI and Nox-1 levels and cardiometabolic risk factors. Results: 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<sup>−/−</sup> 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. Conclusions: We show that PDI and Nox-1 cooperate to control platelet function and are associated with cardiometabolic risk factors.https://www.mdpi.com/2076-3921/10/3/497plateletsprotein disulphide isomeraseNADPH oxidasemetabolic syndromeredox biology |
| spellingShingle | Renato Simões Gaspar Tanya Sage Gemma Little Neline Kriek Giordano Pula Jonathan M. Gibbins Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors Antioxidants platelets protein disulphide isomerase NADPH oxidase metabolic syndrome redox biology |
| title | Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors |
| title_full | Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors |
| title_fullStr | Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors |
| title_full_unstemmed | Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors |
| title_short | Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors |
| title_sort | protein disulphide isomerase and nadph oxidase 1 cooperate to control platelet function and are associated with cardiometabolic disease risk factors |
| topic | platelets protein disulphide isomerase NADPH oxidase metabolic syndrome redox biology |
| url | https://www.mdpi.com/2076-3921/10/3/497 |
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