RBC Rpl13a snoRNAs guides 2'-O-methylation on peroxidasin mRNA promoting venous thrombosis in aging.

IF 5.5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis Pub Date : 2025-03-07 DOI:10.1016/j.jtha.2025.02.036

Waseem Chauhan, Sudharshan Sj, Shirin Ferdowsi, Akib Sohel, Rahima Zennadi

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引用次数: 0

Abstract

Background: Oxidative stress is one of the aging hallmarks. Small non-coding nucleolar RNAs (snoRNAs) of the ribosomal protein L13a (Rpl13a) locus are master regulators of reactive oxygen species (ROS) and oxidative stress, and their loss protects mice from diabetes. Yet, whether excess ROS in RBCs is regulated by Rpl13a snoRNAs in aging and mediate venous thrombosis (VT)/thromboembolism (VT/E) is unknown.

Objectives: We investigated if RBCs retain Rpl13a snoRNAs, and contribute to RBC ROS-mediated VT in a mid-life stage population.

Patients/methods: Blood samples were collected from healthy mid-life stage (55-68 years old) and young (21-30 years old) adults, VT/E patients, and young wild type (WT) mice at 12-24 weeks of age, and aged WT and aged Rpl3a snoRNA knockout mice at 72-96 weeks of age (equivalent to humans 21-30 and 55-68 years old, respectively).

Results: RBCs from mid-life stage adults, and VT/E patients showed higher ROS production and prothrombotic potential than the younger cohort. RBC ROS levels and prothrombotic potential were associated with abnormal Rpl13a snoRNAs levels. In aging, Rpl13a snoRNAs regulated human and murine RBC ROS levels and prothrombic activation by modulating peroxidase activity. This was due largely to Rpl13a snoRNAs-guided 2'-O-methylation on RBC peroxidasin (Pxdn) mRNA; a modification that inhibited the mRNA translation and Pxdn activity. In vivo Rpl13a snoRNA knockout in aged mice blunted RBC ROS generation, decreased thrombi size, thrombi RBC content, and RBCs-triggering prothrombin activation.

Conclusion: These findings point out to a novel role of RBC Rpl13a snoRNAs in VT by dysregulating Pxdn expression in aging.

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来源期刊

Journal of Thrombosis and Haemostasis 医学-外周血管病

CiteScore

24.30

自引率

3.80%

发文量

321

审稿时长

1 months

期刊介绍： The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.