Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis
Thromboembolism resulting from platelet dysfunction constitutes a significant contributor to the development of cardiovascular disease. Sirtuin 6 (SIRT6), an essential NAD+-dependent enzyme, has been linked to arterial thrombosis when absent in endothelial cells. In the present study, we have confir...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1268708/full |
| _version_ | 1797387764935688192 |
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| author | Yanli Liu Tao Wang Qilong Zhou Guang Xin Hai Niu Fan Li Yilan Wang Shiyi Li Yuman Dong Kun Zhang Lijuan Feng Wei Fu Boli Zhang Wen Huang |
| author_facet | Yanli Liu Tao Wang Qilong Zhou Guang Xin Hai Niu Fan Li Yilan Wang Shiyi Li Yuman Dong Kun Zhang Lijuan Feng Wei Fu Boli Zhang Wen Huang |
| author_sort | Yanli Liu |
| collection | DOAJ |
| description | Thromboembolism resulting from platelet dysfunction constitutes a significant contributor to the development of cardiovascular disease. Sirtuin 6 (SIRT6), an essential NAD+-dependent enzyme, has been linked to arterial thrombosis when absent in endothelial cells. In the present study, we have confirmed the presence of SIRT6 protein in anucleated platelets. However, the precise regulatory role of platelet endogenous SIRT6 in platelet activation and thrombotic processes has remained uncertain. Herein, we present compelling evidence demonstrating that platelets isolated from SIRT6-knockout mice (SIRT6−/−) exhibit a notable augmentation in thrombin-induced platelet activation, aggregation, and clot retraction. In contrast, activation of SIRT6 through specific agonist treatment (UBCS039) confers a pronounced protective effect on platelet activation and arterial thrombosis. Moreover, in platelet adoptive transfer experiments between wild-type (WT) and SIRT6−/− mice, the loss of SIRT6 in platelets significantly prolongs the mean thrombus occlusion time in a FeCl3-induced arterial thrombosis mouse model. Mechanistically, we have identified that SIRT6 deficiency in platelets leads to the enhanced expression and release of proprotein convertase subtilisin/kexin type 9 (PCSK9), subsequently activating the platelet activation-associated mitogen-activated protein kinase (MAPK) signaling pathway. These findings collectively unveil a novel protective role of platelet endogenous SIRT6 in platelet activation and thrombosis. This protective effect is, at least in part, attributed to the inhibition of platelet PCSK9 secretion and mitogen-activated protein kinase signaling transduction. Our study provides valuable insights into the intricate interplay between SIRT6 and platelet function, shedding light on potential therapeutic avenues for managing thrombotic disorders. |
| first_indexed | 2024-03-08T22:29:49Z |
| format | Article |
| id | doaj.art-e11667b9023046b8b18c45a7f6b48541 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-08T22:29:49Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-e11667b9023046b8b18c45a7f6b485412023-12-18T06:45:14ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-12-011410.3389/fphar.2023.12687081268708Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosisYanli Liu0Tao Wang1Qilong Zhou2Guang Xin3Hai Niu4Fan Li5Yilan Wang6Shiyi Li7Yuman Dong8Kun Zhang9Lijuan Feng10Wei Fu11Boli Zhang12Wen Huang13Department of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaInnovative Chinese Medicine Academician Workstation, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, ChinaThromboembolism resulting from platelet dysfunction constitutes a significant contributor to the development of cardiovascular disease. Sirtuin 6 (SIRT6), an essential NAD+-dependent enzyme, has been linked to arterial thrombosis when absent in endothelial cells. In the present study, we have confirmed the presence of SIRT6 protein in anucleated platelets. However, the precise regulatory role of platelet endogenous SIRT6 in platelet activation and thrombotic processes has remained uncertain. Herein, we present compelling evidence demonstrating that platelets isolated from SIRT6-knockout mice (SIRT6−/−) exhibit a notable augmentation in thrombin-induced platelet activation, aggregation, and clot retraction. In contrast, activation of SIRT6 through specific agonist treatment (UBCS039) confers a pronounced protective effect on platelet activation and arterial thrombosis. Moreover, in platelet adoptive transfer experiments between wild-type (WT) and SIRT6−/− mice, the loss of SIRT6 in platelets significantly prolongs the mean thrombus occlusion time in a FeCl3-induced arterial thrombosis mouse model. Mechanistically, we have identified that SIRT6 deficiency in platelets leads to the enhanced expression and release of proprotein convertase subtilisin/kexin type 9 (PCSK9), subsequently activating the platelet activation-associated mitogen-activated protein kinase (MAPK) signaling pathway. These findings collectively unveil a novel protective role of platelet endogenous SIRT6 in platelet activation and thrombosis. This protective effect is, at least in part, attributed to the inhibition of platelet PCSK9 secretion and mitogen-activated protein kinase signaling transduction. Our study provides valuable insights into the intricate interplay between SIRT6 and platelet function, shedding light on potential therapeutic avenues for managing thrombotic disorders.https://www.frontiersin.org/articles/10.3389/fphar.2023.1268708/fullplatelet activationcardiovascular-related diseaseSIRT6thrombosisMAPK |
| spellingShingle | Yanli Liu Tao Wang Qilong Zhou Guang Xin Hai Niu Fan Li Yilan Wang Shiyi Li Yuman Dong Kun Zhang Lijuan Feng Wei Fu Boli Zhang Wen Huang Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis Frontiers in Pharmacology platelet activation cardiovascular-related disease SIRT6 thrombosis MAPK |
| title | Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis |
| title_full | Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis |
| title_fullStr | Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis |
| title_full_unstemmed | Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis |
| title_short | Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis |
| title_sort | endogenous sirt6 in platelets negatively regulates platelet activation and thrombosis |
| topic | platelet activation cardiovascular-related disease SIRT6 thrombosis MAPK |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1268708/full |
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