Potential and limitations of PKA/ PKG inhibitors for platelet studies

Shpakova, Valentina; Rukoyatkina, Natalia; Walter, Ulrich; Gambaryan, Stepan

doi:10.1080/09537104.2021.2003316

Cited by 2 publications

(3 citation statements)

References 32 publications

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“…In addition, we established that VASP phosphorylation stimulated by the tested aglycones may be significantly suppressed by H89, a specific PKA The observed inhibitory effect of these aglycones appeared as time-(1-30 min) and dose-dependent (5-100 µM). In addition, we established that VASP phosphorylation stimulated by the tested aglycones may be significantly suppressed by H89, a specific PKA inhibitor that may also inhibit PKG [75,76] (Figure 8). We concluded that the flavonoid aglycones exhibit antiplatelet effects mediated by the activation of the adenylate cyclase (AC)/cAMP/PKA and/or guanylate cyclase (GC)/cGMP/PKG signaling systems.…”

Section: Flavonoid Aglycones Activate Cyclic Nucleotide-mediated Sign...mentioning

confidence: 88%

“…We concluded that the flavonoid aglycones exhibit antiplatelet effects mediated by the activation of the adenylate cyclase (AC)/cAMP/PKA and/or guanylate cyclase (GC)/cGMP/PKG signaling systems. inhibitor that may also inhibit PKG [75,76] (Figure 8). We concluded that the flavonoid aglycones exhibit antiplatelet effects mediated by the activation of the adenylate cyclas (AC)/cAMP/PKA and/or guanylate cyclase (GC)/cGMP/PKG signaling systems.…”

Section: Flavonoid Aglycones Activate Cyclic Nucleotide-mediated Sign...mentioning

confidence: 99%

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

Balykina,

Naida,

Kirkgöz

et al. 2024

IJMS

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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.

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Section: Flavonoid Aglycones Activate Cyclic Nucleotide-mediated Sign...mentioning

confidence: 88%

Section: Flavonoid Aglycones Activate Cyclic Nucleotide-mediated Sign...mentioning

confidence: 99%

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

Balykina,

Naida,

Kirkgöz

et al. 2024

IJMS

Self Cite

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“…Activation of PKA/PKG can be monitored by the phosphorylation of their substrate proteins. In platelets, vasodilator-stimulated phosphoprotein (VASP) is an established substrate of these kinases which is phosphorylated by PKA and PKG [26]. Flavonoids could modulate cyclic nucleotide concentrations in different cell types, including platelets [27].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Isolation and Characterization of a New Flavone C-glycoside Isoembinin from Iris lacteal along with its Effects on Platelet Activation

et al. 2022

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One new compound isoembinin 1 along with ten known compounds 2-11 were isolated from the terrestrial parts of Iris lactea Pall. All of the compound structures were determined through extensive 1D and 2D NMR experiments along with HR-ESIMS analysis and comparison with literature data. Because many flavonoids exert antiplatelet and antioxidant activity we tested the effects of the isolated flavone C-glycosides 1-9 on platelet activation and reactive oxygen species (ROS) production. Platelet reactivity was assessed by activation of αIIbβ3 integrins activation and ROS production by DCF-DA fluorescence. For the analysis of whether protein kinase A or G are involved in the platelet inhibition, the activity of these kinases was analyzed by phosphorylation of their common substrate in platelets. In all experiments apigenin, which inhibit platelet activation was used as a positive control. All isolated flavone C-glycosides inhibited platelet αIIbβ3 integrins activation with IC50 in the µM range, however this inhibitory effect was found to not be mediated through the prevention of ROS formation or by the activation of cyclic nucleotide pathways. Structure-activity comparison between apigenin and compounds 1-9 shows that the presence of C-glycoside and O-glycoside residues on the aglycone apigenin diminish the degree of platelet inhibition.

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Potential and limitations of PKA/ PKG inhibitors for platelet studies

Cited by 2 publications

References 32 publications

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

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

Isolation and Characterization of a New Flavone C-glycoside Isoembinin from Iris lacteal along with its Effects on Platelet Activation

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