The protein disulphide isomerase inhibitor CxxCpep modulates oxidative burst and mitochondrial function in platelets

Gaspar, Renato Simões; Mansilla, Santiago; Vieira, Victor A.; Silva, Ludmila B. da; Gibbins, Jonathan M.; Castro, Laura; Trostchansky, Andrés; Paes, Antonio Marcus de Andrade

doi:10.1016/j.freeradbiomed.2021.07.011

Cited by 4 publications

(6 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most relevant processes regulated by P4HB and PDIA3 in platelets include, apart from cell structure organization, protein folding, ER stress, and the activation of the apoptotic pathways (panel F Figures 3-5). As expected, since PDI regulates oxidant species formation in different cell types [32,33], the formation of ROS is also regulated by PDI activity [34]. ROS formation is important in regulating platelet function and aggregant capacity.…”

Section: Biological Function Enrichmentsupporting

confidence: 65%

An Overview of Two Old Friends Associated with Platelet Redox Signaling, the Protein Disulfide Isomerase and NADPH Oxidase

Trostchansky

Alarcón

2023

Biomolecules

Self Cite

View full text Add to dashboard Cite

Oxidative stress participates at the baseline of different non-communicable pathologies such as cardiovascular diseases. Excessive formation of reactive oxygen species (ROS), above the signaling levels necessary for the correct function of organelles and cells, may contribute to the non-desired effects of oxidative stress. Platelets play a relevant role in arterial thrombosis, by aggregation triggered by different agonists, where excessive ROS formation induces mitochondrial dysfunction and stimulate platelet activation and aggregation. Platelet is both a source and a target of ROS, thus we aim to analyze both the platelet enzymes responsible for ROS generation and their involvement in intracellular signal transduction pathways. Among the proteins involved in these processes are Protein Disulphide Isomerase (PDI) and NADPH oxidase (NOX) isoforms. By using bioinformatic tools and information from available databases, a complete bioinformatic analysis of the role and interactions of PDI and NOX in platelets, as well as the signal transduction pathways involved in their effects was performed. We focused the study on analyzing whether these proteins collaborate to control platelet function. The data presented in the current manuscript support the role that PDI and NOX play on activation pathways necessary for platelet activation and aggregation, as well as on the platelet signaling imbalance produced by ROS production. Our data could be used to design specific enzyme inhibitors or a dual inhibition for these enzymes with an antiplatelet effect to design promising treatments for diseases involving platelet dysfunction.

show abstract

Section: Biological Function Enrichmentsupporting

confidence: 65%

An Overview of Two Old Friends Associated with Platelet Redox Signaling, the Protein Disulfide Isomerase and NADPH Oxidase

Trostchansky

Alarcón

2023

Biomolecules

Self Cite

View full text Add to dashboard Cite

show abstract

“…Given the recent evidence that the inhibition of peri/epicellular PDIA1 inhibited platelet aggregation in parallel with intracellular oxidative burst and mitochondrial respiration, 47 and that PDIA1 regulate Nox1 activity in vascular smooth muscle cells and in endothelial cells, 29 , 48 , 49 it is possible that PDIA1 in platelets also regulates Nox1‐mediated production of ROS. Gimenez et al 29 demonstrated that in vascular smooth muscle cell PDIA1 increased phosphorylation of p47phox subunit in Nox1 activation.…”

Section: Discussionmentioning

confidence: 99%

“…45,46 Additionally, COX may produce ROS 40 and peroxy compounds, which could oxidize H 2 DCF-DA. 45 Given the recent evidence that the inhibition of peri/epicellular PDIA1 inhibited platelet aggregation in parallel with intracellular oxidative burst and mitochondrial respiration, 47 and that PDIA1 regulate Nox1 activity in vascular smooth muscle cells and in endothelial cells, 29,48,49 it is possible that PDIA1 in platelets also regulates Nox1mediated production of ROS. Gimenez et al 29 reduced TxA 2 production following GPVI receptor stimulation.…”

Section: Importantly Bepristat Potently Reduced the Production Of Ros...mentioning

confidence: 99%

Protein disulfide isomerase‐A1 regulates intraplatelet reactive oxygen species–thromboxane A2‐dependent pathway in human platelets

Przyborowski

Kurpińska

Wójkowska

et al. 2022

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Background Platelet‐derived protein disulfide isomerase 1 (PDIA1) regulates thrombus formation, but its role in the regulation of platelet function is not fully understood. Aims The aim of this study was to characterize the role of PDIA1 in human platelets. Methods Proteomic analysis of PDI isoforms in platelets was performed using liquid chromatography tandem mass spectometry, and the expression of PDIs on platelets in response to collagen, TRAP‐14, or ADP was measured with flow cytometry. The effects of bepristat, a selective PDIA1 inhibitor, on platelet aggregation, expression of platelet surface activation markers, thromboxane A2 (TxA2), and reactive oxygen species (ROS) generation were evaluated by optical aggregometry, flow cytometry, ELISA, and dihydrodichlorofluorescein diacetate‐based fluorescent assay, respectively. Results PDIA1 was less abundant compared with PDIA3 in resting platelets and platelets stimulated with TRAP‐14, collagen, or ADP. Collagen, but not ADP, induced a significant increase in PDIA1 expression. Bepristat potently inhibited the aggregation of washed platelets induced by collagen or convulxin, but only weakly inhibited platelet aggregation induced by TRAP‐14 or thrombin, and had the negligible effect on platelet aggregation induced by arachidonic acid. Inhibition of PDIA1 by bepristat resulted in the reduction of TxA2 and ROS production in collagen‐ or thrombin‐stimulated platelets. Furthermore, bepristat reduced the activation of αIIbβ3 integrin and expression of P‐selectin. Conclusions PDIA1 acts as an intraplatelet regulator of the ROS‐TxA2 pathway in collagen‐GP VI receptor‐mediated platelet activation that is a mechanistically distinct pathway from extracellular regulation of αIIbβ3 integrin by PDIA3.

show abstract

“…The MitoSOX probe was used to identify mitochondrial ROS production specifically [ 68 ]. Washed platelets (50 × 10 6 platelets/mL) were labeled with the MitoSOX® Red probe (Invitrogen, Carlsbad, CA, USA) 10 μM and incubated for 20 min at 37 °C protected from light [ 69 ]. After, compounds (1, 5, and 10 μM) were added to the platelets and incubated for 10 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Linking triphenylphosphonium cation to a bicyclic hydroquinone improves their antiplatelet effect via the regulation of mitochondrial function

Méndez,

Tellería,

Monroy-Cárdenas

et al. 2024

Redox Biology

Self Cite

View full text Add to dashboard Cite

The protein disulphide isomerase inhibitor CxxCpep modulates oxidative burst and mitochondrial function in platelets

Cited by 4 publications

References 27 publications

An Overview of Two Old Friends Associated with Platelet Redox Signaling, the Protein Disulfide Isomerase and NADPH Oxidase

An Overview of Two Old Friends Associated with Platelet Redox Signaling, the Protein Disulfide Isomerase and NADPH Oxidase

Protein disulfide isomerase‐A1 regulates intraplatelet reactive oxygen species–thromboxane A2‐dependent pathway in human platelets

Linking triphenylphosphonium cation to a bicyclic hydroquinone improves their antiplatelet effect via the regulation of mitochondrial function

Contact Info

Product

Resources

About