Metformin Serves as a Novel Drug Treatment for Arterial Thrombosis: Inhibitory Mechanisms on Collagen-Induced Human Platelet Activation
Metformin is widely used as first-line medication for type 2 diabetes (T2D), the main disease comorbid with kidney disease, cardiovascular diseases (CVDs), and retinopathy. Platelets are crucial in platelet-dependent arterial thrombosis, which causes CVDs and cerebrovascular diseases. Research indic...
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| Format: | Article |
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MDPI AG
2022-07-01
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| Online Access: | https://www.mdpi.com/2076-3417/12/15/7426 |
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| author | Yi Chang Wei-Chieh Huang Chia-Yuan Hsu Chih-Wei Hsia Thanasekaran Jayakumar Cheng-Ying Hsieh Wan-Jung Lu Chao-Chien Chang |
| author_facet | Yi Chang Wei-Chieh Huang Chia-Yuan Hsu Chih-Wei Hsia Thanasekaran Jayakumar Cheng-Ying Hsieh Wan-Jung Lu Chao-Chien Chang |
| author_sort | Yi Chang |
| collection | DOAJ |
| description | Metformin is widely used as first-line medication for type 2 diabetes (T2D), the main disease comorbid with kidney disease, cardiovascular diseases (CVDs), and retinopathy. Platelets are crucial in platelet-dependent arterial thrombosis, which causes CVDs and cerebrovascular diseases. Research indicates that metformin may improve these diseases; metformin reportedly reduced platelet activation in rats. However, no reports have included human platelets. We investigated the mechanisms underlying metformin’s effects on platelet activation by using human platelets and evaluated its in vivo effectiveness in experimental mice. Metformin inhibited platelet aggregation stimulated by collagen but not by arachidonic acid, U46619, or thrombin. Metformin suppressed ATP release, [Ca<sup>2+</sup>]i mobilization, and P-selectin expression, as well as phospholipase C (PLC)γ2/protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation. Metformin did not affect vasodilator-stimulated phosphoprotein (VASP) phosphorylation. In the animal studies, metformin reduced acute pulmonary thromboembolism mortality without increasing bleeding times. These results provide insights into the role and mechanisms of metformin in human platelet activation. Metformin decreased platelet activation by interfering with the PLCγ2/PKC, PI3K/Akt/GSK3β, and p38 MAPK pathways through a VASP-independent mechanism. Metformin demonstrates promise as a new class of antiplatelet agent that can inhibit platelet activation. |
| first_indexed | 2024-03-09T10:10:04Z |
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| language | English |
| last_indexed | 2024-03-09T10:10:04Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Applied Sciences |
| spelling | doaj.art-05f82dca96554b92a63d7546fafa9f0b2023-12-01T22:49:36ZengMDPI AGApplied Sciences2076-34172022-07-011215742610.3390/app12157426Metformin Serves as a Novel Drug Treatment for Arterial Thrombosis: Inhibitory Mechanisms on Collagen-Induced Human Platelet ActivationYi Chang0Wei-Chieh Huang1Chia-Yuan Hsu2Chih-Wei Hsia3Thanasekaran Jayakumar4Cheng-Ying Hsieh5Wan-Jung Lu6Chao-Chien Chang7Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, 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, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Ecology and Environmental Sciences, Pondicherry University, Puducherry 605014, 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, TaiwanSchool of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, TaiwanMetformin is widely used as first-line medication for type 2 diabetes (T2D), the main disease comorbid with kidney disease, cardiovascular diseases (CVDs), and retinopathy. Platelets are crucial in platelet-dependent arterial thrombosis, which causes CVDs and cerebrovascular diseases. Research indicates that metformin may improve these diseases; metformin reportedly reduced platelet activation in rats. However, no reports have included human platelets. We investigated the mechanisms underlying metformin’s effects on platelet activation by using human platelets and evaluated its in vivo effectiveness in experimental mice. Metformin inhibited platelet aggregation stimulated by collagen but not by arachidonic acid, U46619, or thrombin. Metformin suppressed ATP release, [Ca<sup>2+</sup>]i mobilization, and P-selectin expression, as well as phospholipase C (PLC)γ2/protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation. Metformin did not affect vasodilator-stimulated phosphoprotein (VASP) phosphorylation. In the animal studies, metformin reduced acute pulmonary thromboembolism mortality without increasing bleeding times. These results provide insights into the role and mechanisms of metformin in human platelet activation. Metformin decreased platelet activation by interfering with the PLCγ2/PKC, PI3K/Akt/GSK3β, and p38 MAPK pathways through a VASP-independent mechanism. Metformin demonstrates promise as a new class of antiplatelet agent that can inhibit platelet activation.https://www.mdpi.com/2076-3417/12/15/7426human plateletsmetforminp38 MAPKPLCγ2pulmonary thrombosisPI3K/Akt/GSK3β |
| spellingShingle | Yi Chang Wei-Chieh Huang Chia-Yuan Hsu Chih-Wei Hsia Thanasekaran Jayakumar Cheng-Ying Hsieh Wan-Jung Lu Chao-Chien Chang Metformin Serves as a Novel Drug Treatment for Arterial Thrombosis: Inhibitory Mechanisms on Collagen-Induced Human Platelet Activation Applied Sciences human platelets metformin p38 MAPK PLCγ2 pulmonary thrombosis PI3K/Akt/GSK3β |
| title | Metformin Serves as a Novel Drug Treatment for Arterial Thrombosis: Inhibitory Mechanisms on Collagen-Induced Human Platelet Activation |
| title_full | Metformin Serves as a Novel Drug Treatment for Arterial Thrombosis: Inhibitory Mechanisms on Collagen-Induced Human Platelet Activation |
| title_fullStr | Metformin Serves as a Novel Drug Treatment for Arterial Thrombosis: Inhibitory Mechanisms on Collagen-Induced Human Platelet Activation |
| title_full_unstemmed | Metformin Serves as a Novel Drug Treatment for Arterial Thrombosis: Inhibitory Mechanisms on Collagen-Induced Human Platelet Activation |
| title_short | Metformin Serves as a Novel Drug Treatment for Arterial Thrombosis: Inhibitory Mechanisms on Collagen-Induced Human Platelet Activation |
| title_sort | metformin serves as a novel drug treatment for arterial thrombosis inhibitory mechanisms on collagen induced human platelet activation |
| topic | human platelets metformin p38 MAPK PLCγ2 pulmonary thrombosis PI3K/Akt/GSK3β |
| url | https://www.mdpi.com/2076-3417/12/15/7426 |
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