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Rpl13a snoRNAs-regulated NADPH oxidase 1-dependent ROS generation: A novel RBC pathway mediating complement C3a
Waseem Chauhan1, Shirin Ferdowsi1, S J Sudharshan1
1Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
Free Radical Biology & Medicine
|February 12, 2025
Summary
Aging increases venous thrombosis risk. Red blood cells (RBCs) from older adults show complement C3a deposition, triggering clotting via reactive oxygen species (ROS). Rpl13a snoRNAs regulate this process, offering potential therapeutic targets for thrombosis.
Area of Science:
- Hematology
- Immunology
- Gerontology
Background:
- Adults over 45 face a higher risk of venous thrombosis/thromboembolism.
- Complement activation, linked to oxidative stress, is central to venous thrombosis.
- The role of red blood cells (RBCs) in complement activation and thrombosis in aging remains unclear.
Purpose of the Study:
- To investigate the contribution of RBCs to complement activation and thrombosis in aging.
- To explore the mechanisms linking RBCs, oxidative stress, and venous thrombosis in older adults.
Main Methods:
- Analysis of RBCs from young adults, mid-life adults, and patients with venous thrombosis for complement C3/C3a deposition and NADPH oxidase (Nox)1 expression.
- Assessment of prothrombin activation, reactive oxygen species (ROS) generation, and G protein-coupled receptor kinase 2 (GRK2) activation in RBCs.
- In vivo studies using Rpl13a snoRNA knockout aged mice to evaluate thrombus formation and RBC C3a deposition.
Main Results:
- RBCs from mid-life adults and thrombosis patients exhibited increased C3/C3a deposition and Nox1 expression, correlating with prothrombin activation via ROS and GRK2.
- Interaction of C3/C3a-positive RBCs with endothelial cells elevated endothelial ROS production.
- Rpl13a snoRNAs were identified as key regulators of RBC C3a deposition and prothrombotic activation in aging by modulating Nox1 mRNA expression, with knockout reducing thrombus size in mice.
Conclusions:
- RBCs play a significant role in complement activation and thrombosis in aging.
- Rpl13a snoRNAs are novel regulators of age-associated venous thrombosis by controlling ROS-induced C3a deposition in RBCs.
- Targeting RBC Rpl13a snoRNAs may offer a new therapeutic strategy for preventing venous thrombosis in the elderly.
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