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      Phospholipase Cγ2 Signaling Cascade Contribute to the Antiplatelet Effect of Notoginsenoside Fc

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          Abstract

          Scope: Bleeding, the main drawback of clinically used chemical anti-thrombotic drug is resulted from the unidirectional suppression of platelet activity. Therefore, dual-directional regulatory effect on platelet is the main preponderance of Panax notoginseng over these drugs. The dual-directional regulatory effect should be ascribed to the resourceful Panax notoginseng saponins (PNS). Clarifying the mechanism of main PNS in both inhibiting and promoting platelet aggregation will give a full outlook for the dual-directional regulatory effect. The present study is aimed at explaining the mechanism of Notoginsenoside Fc (Fc), a main PNS, in inhibiting platelet aggregation.

          Methods: In the in vitro study, after incubating platelets with Fc and m-3M3FBS, platelet aggregation was triggered by thrombin, collagen or ADP. Platelet aggregation was measured by aggregometer. Phospholipase Cγ2 (PLCγ2) and protein kinase C (PKC) activities were studied by western blotting. Diacylglycerol (DAG), thromboxane B 2 (TXB 2) and 1,4,5-inositol trisphosphate (IP 3) concentrations were measured by corresponding ELISA kits. Calcium concentrations ([Ca 2+]) were estimated through the fluorescence intensity emitted from Fluo-4. In the in vivo study, thrombus model was induced by FeCl 3. The effect of Fc on thrombosis was evaluated by measurement of protein content and observation of injured blood vessel.

          Results: thrombin, collagen and ADP induced platelet aggregation were all suppressed by incubating platelets with Fc. Platelet PLCγ2 and subsequent DAG-PKC-TXA 2 and IP 3 were down-regulated by Fc as well. However, the basal [Ca 2+] in platelet was not altered by Fc. Nevertheless, thrombin triggered activation of PLCγ2 and subsequent DAG-PKC-TXA 2 and IP 3-[Ca 2+] were all abolished by Fc. Fc also attenuated platelet aggregation and PLCγ2 signaling activation induced by PLC activator, m-3M3FBS. In the in vivo study, FeCl 3 induced thrombosis in rat femoral artery was significantly alleviated by administration of Fc.

          Conclusion: The results above suggested the antiplatelet and antithrombotic effects of Fc are carried out through oppression of PLCγ2 and subsequent DAG-PKC-TXA 2 and IP 3-[Ca 2+]. The present study provided theoretical support for new anti-thrombotic drug exploitation by Panax notoginseng.

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          Triggers, targets and treatments for thrombosis.

          Nigel Mackman (2008)
          Thrombosis--localized clotting of the blood--can occur in the arterial or the venous circulation and has a major medical impact. Acute arterial thrombosis is the proximal cause of most cases of myocardial infarction (heart attack) and of about 80% of strokes, collectively the most common cause of death in the developed world. Venous thromboembolism is the third leading cause of cardiovascular-associated death. The pathogenic changes that occur in the blood vessel wall and in the blood itself resulting in thrombosis are not fully understood. Understanding these processes is crucial for developing safer and more effective antithrombotic drugs.
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            Two disparate ligand-binding sites in the human P2Y1 receptor.

            Dandan Zhang, Zhan-Guo Gao, Kaihua Zhang … (2015)
            In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 Å resolution, and with a non-nucleotide antagonist BPTU at 2.2 Å resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.
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              Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes.

              K Pieper, Frans Van Roy, K O'Grady … (2005)
              Bleeding is a complication of current therapies for acute coronary syndrome (ACS). No studies have examined the effect of bleeding events on clinical outcomes. We analyzed pooled data from 4 multicenter, randomized clinical trials of patients who had ACS (n = 26,452) to determine an association between bleeding severity as measured by the GUSTO scale and 30-day and 6-month mortality rates using Cox proportional hazards modeling that incorporated bleeding as a time-dependent covariate. The analysis was repeated to examine procedure- and non-procedure-related bleeding and after censoring at the time of coronary artery bypass grafting. Of all the patients included, 27.6% had > or =1 bleeding episode. Patients who bled were older and sicker at presentation than were those who did not bleed. Unadjusted rates of 30-day and 6-month mortality increased as bleeding severity increased. There were stepwise increases in the adjusted hazards of 30-day mortality (mild bleeding, hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.3 to 1.9; moderate bleeding, HR 2.7, 95% CI l 2.3 to 3.4; severe bleeding, HR 10.6, 95% CI 8.3 to 13.6) and 6-month mortality (mild bleeding, HR 1.4, 95% CI 1.2 to 1.6; moderate bleeding, HR 2.1, 95% CI 1.8 to 2.4; severe bleeding, HR 7.5, 95% CI 6.1 to 9.3) as bleeding severity increased. Results were consistent after censoring for coronary artery bypass grafting and for procedure- and non-procedure-related bleeds. In conclusion, the GUSTO bleeding classification identifies patients who are at risk for short- and long-term adverse events. Therapies that minimize bleeding risk and maintain an anticoagulant effect may improve outcomes among patients who have ACS.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Pharmacol
                Journal ID (iso-abbrev): Front Pharmacol
                Journal ID (publisher-id): Front. Pharmacol.
                Title: Frontiers in Pharmacology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1663-9812
                Publication date (Electronic): 06 November 2018
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 1293
                Affiliations
                [1] 1Laboratory of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University , Yangling, China
                [2] 2Department of Neurosurgery, The First Hospital of Jilin University , Changchun, China
                [3] 3University of Illinois at Urbana–Champaign , Urbana, IL, United States
                [4] 4Department of Neurosciences, University of California, San Diego School of Medicine , La Jolla, CA, United States
                Author notes

                Edited by: Akio Inui, Kagoshima University, Japan

                Reviewed by: Munekazu Yamakuchi, Kagoshima University, Japan; Xu Wang, Wenzhou Medical University, China; Jianxin Deng, Yangtze University, China

                *Correspondence: Xiaoping Song, sxpxbnl@ 123456163.com

                This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

                Article
                DOI: 10.3389/fphar.2018.01293
                PMC ID: 6232503
                PubMed ID: 30459626
                SO-VID: 311dad2b-73a4-4fbc-8d35-65a4dbd8472f
                Copyright © Copyright © 2018 Liu, Liu, Ding, Liu, Li, He, Zhang, Fan, Ma, Cui and Song.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 04 May 2018
                Date accepted : 22 October 2018
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 34, Pages: 11, Words: 0
                Funding
                Funded by: China Postdoctoral Science Foundation 10.13039/501100002858
                Award ID: 2016M602882
                Funded by: Ministry of Agriculture of the People’s Republic of China 10.13039/501100004573
                Award ID: 201303040
                Funded by: Ministry of Education of the People’s Republic of China 10.13039/501100002338
                Award ID: 2452017297
                Categories
                Subject: Pharmacology
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: panax notoginseng,notoginsenoside fc,platelet aggregation,antiplatelet effect,thrombosis,phospholipase cγ2
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: panax notoginseng, notoginsenoside fc, platelet aggregation, antiplatelet effect, thrombosis, phospholipase cγ2

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