Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases

Balykina, Anna; Naida, Lidia; Kirkgöz, Kürsat; Nikolaev, Viacheslav O.; Fock, Ekaterina; Belyakov, Michael; Whaley, Anastasiia; Whaley, Andrei; Shpakova, Valentina; Rukoyatkina, Natalia; Gambaryan, Stepan

doi:10.3390/ijms25094864

Open AccessArticle

Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases

by

Anna Balykina

^1,2

,

Lidia Naida

³,

Kürsat Kirkgöz

⁴

,

Viacheslav O. Nikolaev

^4,5

,

Ekaterina Fock

¹,

Michael Belyakov

⁶

,

Anastasiia Whaley

^1,7

,

Andrei Whaley

⁷,

Valentina Shpakova

⁸

,

Natalia Rukoyatkina

¹

and

Stepan Gambaryan

^1,*

¹

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg 194223, Russia

²

Faculty of General Medicine, Saint Petersburg State University, Saint Petersburg 199034, Russia

³

Institute of Biomedical Systems and Biotechnologies, Peter the Great Saint Petersburg Polytechnic University, Saint Petersburg 195251, Russia

⁴

Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany

⁵

German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany

⁶

Research Institute of Hygiene, Occupational Pathology and Human Ecology, Saint Petersburg 188663, Russia

⁷

Department of Pharmacognosy, Saint Petersburg State Chemical and Pharmaceutical University, Saint Petersburg 197022, Russia

⁸

Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading RG6 6AS, UK

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2024, 25(9), 4864; https://doi.org/10.3390/ijms25094864

Submission received: 29 March 2024 / Revised: 23 April 2024 / Accepted: 26 April 2024 / Published: 29 April 2024

(This article belongs to the Special Issue New Advances in Thrombosis 2.0)

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Abstract

Flavonoid aglycones are secondary plant metabolites that exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anticancer, and antiplatelet effects. However, the precise molecular mechanisms underlying their inhibitory effect on platelet activation remain poorly understood. In this study, we applied flow cytometry to analyze the effects of six flavonoid aglycones (luteolin, myricetin, quercetin, eriodictyol, kaempferol, and apigenin) on platelet activation, phosphatidylserine externalization, formation of reactive oxygen species, and intracellular esterase activity. We found that these compounds significantly inhibit thrombin-induced platelet activation and decrease formation of reactive oxygen species in activated platelets. The tested aglycones did not affect platelet viability, apoptosis induction, or procoagulant platelet formation. Notably, luteolin, myricetin, quercetin, and apigenin increased thrombin-induced thromboxane synthase activity, which was analyzed by a spectrofluorimetric method. Our results obtained from Western blot analysis and liquid chromatography–tandem mass spectrometry demonstrated that the antiplatelet properties of the studied phytochemicals are mediated by activation of cyclic nucleotide-dependent signaling pathways. Specifically, we established by using Förster resonance energy transfer that the molecular mechanisms are, at least partly, associated with the inhibition of phosphodiesterases 2 and/or 5. These findings underscore the therapeutic potential of flavonoid aglycones for clinical application as antiplatelet agents.

Keywords: antiplatelet therapy; platelets; flavonoids; thromboxane synthase (TxS); cyclic adenosine monophosphate (cAMP); cyclic guanosine monophosphate (cGMP); phosphodiesterase (PDE); PDE inhibitors; protein kinase A (PKA); protein kinase G (PKG)

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MDPI and ACS Style

Balykina, A.; Naida, L.; Kirkgöz, K.; Nikolaev, V.O.; Fock, E.; Belyakov, M.; Whaley, A.; Whaley, A.; Shpakova, V.; Rukoyatkina, N.; et al. Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases. Int. J. Mol. Sci. 2024, 25, 4864. https://doi.org/10.3390/ijms25094864

AMA Style

Balykina A, Naida L, Kirkgöz K, Nikolaev VO, Fock E, Belyakov M, Whaley A, Whaley A, Shpakova V, Rukoyatkina N, et al. Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases. International Journal of Molecular Sciences. 2024; 25(9):4864. https://doi.org/10.3390/ijms25094864

Chicago/Turabian Style

Balykina, Anna, Lidia Naida, Kürsat Kirkgöz, Viacheslav O. Nikolaev, Ekaterina Fock, Michael Belyakov, Anastasiia Whaley, Andrei Whaley, Valentina Shpakova, Natalia Rukoyatkina, and et al. 2024. "Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases" International Journal of Molecular Sciences 25, no. 9: 4864. https://doi.org/10.3390/ijms25094864

APA Style

Balykina, A., Naida, L., Kirkgöz, K., Nikolaev, V. O., Fock, E., Belyakov, M., Whaley, A., Whaley, A., Shpakova, V., Rukoyatkina, N., & Gambaryan, S. (2024). Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases. International Journal of Molecular Sciences, 25(9), 4864. https://doi.org/10.3390/ijms25094864

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Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases

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