Role of the NO-GC/cGMP signaling pathway in platelet biomechanics
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| Názov: | Role of the NO-GC/cGMP signaling pathway in platelet biomechanics |
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| Autori: | Aylin Balmes, Johanna G. Rodríguez, Jan Seifert, Daniel Pinto-Quintero, Akif A. Khawaja, Marta Boffito, Maike Frye, Andreas Friebe, Michael Emerson, Francesca Seta, Robert Feil, Susanne Feil, Tilman E. Schäffer |
| Zdroj: | Platelets, Vol 35, Iss 1 (2024) |
| Informácie o vydavateľovi: | Cold Spring Harbor Laboratory, 2023. |
| Rok vydania: | 2023 |
| Predmety: | Blood Platelets, 0301 basic medicine, Platelet Aggregation, Cellular stiffness, Platelet Activation, Nitric Oxide, Biomechanical Phenomena, 3. Good health, inhibition of platelet activation, Mice, 03 medical and health sciences, 0302 clinical medicine, Guanylate Cyclase, NO-sensitive guanylyl cyclase (NO-GC) enzyme, Humans, Animals, cyclic guanosine monophosphate (cGMP), Diseases of the blood and blood-forming organs, platelet shape, RC633-647.5, Cyclic GMP, Signal Transduction |
| Popis: | Cyclic guanosine monophosphate (cGMP) is a second messenger produced by the NO-sensitive guanylyl cyclase (NO-GC) enzyme. In platelets, the NO-GC/cGMP pathway inhibits aggregation. One aspect of the inhibitory mechanism involves changes in the cytoskeleton; however, the molecular mechanisms underlying platelet inhibition and its correlation with cytoskeletal cellular stiffness are poorly understood.We measured the cellular stiffness of individual platelets after treatment with the NO-GC stimulator riociguat or the NO-GC activator cinaciguat, using scanning ion conductance microscopy (SICM). We quantified changes in platelet shape using deep learning-based platelet morphometry. Cytoskeletal actin polymerization and platelet activation were measured by co-immunostaining F-actin and P-selectin, respectively. To test for clinical applicability of NO-GC stimulators in the context of increased thrombogenicity risk, we investigated the effect of riociguat on platelets from human immunodeficiency virus (HIV)-positive patients taking abacavir sulphate (ABC)-containing regimens, compared with HIV-negative volunteers.Stimulation of human and murine platelets with the NO-GC stimulator riociguat or with the NO-GC activator cinaciguat downregulated P-selectin expression, decreased F-actin polymerization, and decreased cellular stiffness by ≈50%, compared to vehicle control. In addition, platelets became more circular, indicating decreased activation. Riociguat did not cause any change in platelet aggregation or circularity in HIV-positive patients taking ABC-containing regimens.These results corroborate a functional role of the NO-GC enzyme in platelet biomechanics (cellular stiffness) in correlation with the inhibition of platelet activation and morphological changes. The observed changes in stiffness and platelet shape therefore demonstrate the possibility of pharmacologically targeting the NO-GC/cGMP pathway. |
| Druh dokumentu: | Article |
| ISSN: | 1369-1635 0953-7104 |
| DOI: | 10.1101/2023.04.28.538670 |
| DOI: | 10.1080/09537104.2024.2313359 |
| DOI: | 10.15496/publikation-100164 |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/38353233 https://doaj.org/article/676e9f37d7ea490688f68b125537d8f7 |
| Rights: | CC BY |
| Prístupové číslo: | edsair.doi.dedup.....3fb2bd8f87f9e7e4b27b30f6c2edb2d7 |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Cyclic guanosine monophosphate (cGMP) is a second messenger produced by the NO-sensitive guanylyl cyclase (NO-GC) enzyme. In platelets, the NO-GC/cGMP pathway inhibits aggregation. One aspect of the inhibitory mechanism involves changes in the cytoskeleton; however, the molecular mechanisms underlying platelet inhibition and its correlation with cytoskeletal cellular stiffness are poorly understood.We measured the cellular stiffness of individual platelets after treatment with the NO-GC stimulator riociguat or the NO-GC activator cinaciguat, using scanning ion conductance microscopy (SICM). We quantified changes in platelet shape using deep learning-based platelet morphometry. Cytoskeletal actin polymerization and platelet activation were measured by co-immunostaining F-actin and P-selectin, respectively. To test for clinical applicability of NO-GC stimulators in the context of increased thrombogenicity risk, we investigated the effect of riociguat on platelets from human immunodeficiency virus (HIV)-positive patients taking abacavir sulphate (ABC)-containing regimens, compared with HIV-negative volunteers.Stimulation of human and murine platelets with the NO-GC stimulator riociguat or with the NO-GC activator cinaciguat downregulated P-selectin expression, decreased F-actin polymerization, and decreased cellular stiffness by ≈50%, compared to vehicle control. In addition, platelets became more circular, indicating decreased activation. Riociguat did not cause any change in platelet aggregation or circularity in HIV-positive patients taking ABC-containing regimens.These results corroborate a functional role of the NO-GC enzyme in platelet biomechanics (cellular stiffness) in correlation with the inhibition of platelet activation and morphological changes. The observed changes in stiffness and platelet shape therefore demonstrate the possibility of pharmacologically targeting the NO-GC/cGMP pathway. |
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| ISSN: | 13691635 09537104 |
| DOI: | 10.1101/2023.04.28.538670 |