Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis

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

doi:10.3389/fphar.2023.1268708

Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis

Front Pharmacol. 2023 Dec 18:14:1268708. doi: 10.3389/fphar.2023.1268708. eCollection 2023.

Authors

Yanli Liu^#¹, Tao Wang^#¹, Qilong Zhou^#¹, Guang Xin¹, Hai Niu¹, Fan Li¹, Yilan Wang¹, Shiyi Li¹, Yuman Dong¹, Kun Zhang¹, Lijuan Feng¹, Wei Fu¹, Boli Zhang², Wen Huang¹

Affiliations

¹ Department 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, China.
² Innovative Chinese Medicine Academician Workstation, West China Hospital, Sichuan University, Chengdu, China.

^# Contributed equally.

Abstract

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.

Keywords: MAPK; SIRT6; cardiovascular-related disease; platelet activation; thrombosis.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was financed by Grant-in-aid for scientific research from the National Natural Science Foundation of China (Grant No. 81973580), the COVID-19 Science and Technology Emergency Project of Sichuan Province of China (Grant No. 2021YFS0408), the Key Technology Research and Development Program of Sichuan Province of China (Grant No’s 2022YFS0425 and 2022YFS0426), 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. ZYXY21002), Key R&D project of Science and Technology Department of Sichuan Province (Grant No. 2022YFS0335).