Rutaecarpine, an Alkaloid from <i>Evodia rutaecarpa</i>, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP—Independent Mechanism
The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. <i>Evodia rutaecarpa</i> (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bio...
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/20/11109 |
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| author | Chun-Jen Huang Wei-Chieh Huang Wei-Ting Lin Lan-Hsin Shu Joen-Rong Sheu Oanh-Thi Tran Chih-Wei Hsia Thanasekaran Jayakumar Periyakali Saravana Bhavan Cheng-Ying Hsieh Chao-Chien Chang |
| author_facet | Chun-Jen Huang Wei-Chieh Huang Wei-Ting Lin Lan-Hsin Shu Joen-Rong Sheu Oanh-Thi Tran Chih-Wei Hsia Thanasekaran Jayakumar Periyakali Saravana Bhavan Cheng-Ying Hsieh Chao-Chien Chang |
| author_sort | Chun-Jen Huang |
| collection | DOAJ |
| description | The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. <i>Evodia rutaecarpa</i> (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1–5 μM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca<sup>2+</sup>]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3β pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders. |
| first_indexed | 2024-03-10T06:30:56Z |
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| language | English |
| last_indexed | 2024-03-10T06:30:56Z |
| publishDate | 2021-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9345c6e3d7bf4f02afb245f5cc1412ca2023-11-22T18:34:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122201110910.3390/ijms222011109Rutaecarpine, an Alkaloid from <i>Evodia rutaecarpa</i>, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP—Independent MechanismChun-Jen Huang0Wei-Chieh Huang1Wei-Ting Lin2Lan-Hsin Shu3Joen-Rong Sheu4Oanh-Thi Tran5Chih-Wei Hsia6Thanasekaran Jayakumar7Periyakali Saravana Bhavan8Cheng-Ying Hsieh9Chao-Chien Chang10Department of Anesthesiology and Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 110, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Nutrition, Chung Shan Medical University, Taichung 402, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanInternational Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Zoology, Bharathiar University, Coimbatore 641046, Tamil Nadu, IndiaDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanThe role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. <i>Evodia rutaecarpa</i> (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1–5 μM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca<sup>2+</sup>]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3β pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.https://www.mdpi.com/1422-0067/22/20/11109cyclic nucleotidehuman plateletshydroxyl radicalrutaecarpineMAPKmicrovascular thrombosis |
| spellingShingle | Chun-Jen Huang Wei-Chieh Huang Wei-Ting Lin Lan-Hsin Shu Joen-Rong Sheu Oanh-Thi Tran Chih-Wei Hsia Thanasekaran Jayakumar Periyakali Saravana Bhavan Cheng-Ying Hsieh Chao-Chien Chang Rutaecarpine, an Alkaloid from <i>Evodia rutaecarpa</i>, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP—Independent Mechanism International Journal of Molecular Sciences cyclic nucleotide human platelets hydroxyl radical rutaecarpine MAPK microvascular thrombosis |
| title | Rutaecarpine, an Alkaloid from <i>Evodia rutaecarpa</i>, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP—Independent Mechanism |
| title_full | Rutaecarpine, an Alkaloid from <i>Evodia rutaecarpa</i>, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP—Independent Mechanism |
| title_fullStr | Rutaecarpine, an Alkaloid from <i>Evodia rutaecarpa</i>, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP—Independent Mechanism |
| title_full_unstemmed | Rutaecarpine, an Alkaloid from <i>Evodia rutaecarpa</i>, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP—Independent Mechanism |
| title_short | Rutaecarpine, an Alkaloid from <i>Evodia rutaecarpa</i>, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3β Signal Axis through a Cyclic Nucleotides/VASP—Independent Mechanism |
| title_sort | rutaecarpine an alkaloid from i evodia rutaecarpa i can prevent platelet activation in humans and reduce microvascular thrombosis in mice crucial role of the pi3k akt gsk3β signal axis through a cyclic nucleotides vasp independent mechanism |
| topic | cyclic nucleotide human platelets hydroxyl radical rutaecarpine MAPK microvascular thrombosis |
| url | https://www.mdpi.com/1422-0067/22/20/11109 |
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