Alan Nurden: A miR-146a Variant Reveals a New Pathway Linking Platelet Metabolism and Thrombosis
Alan Nurden, Emeritus Research Director at CNRS, Co-Founder of the French National Reference Centre for Inherited Platelet Disorders (CRPP shared a post on LinkedIn about recent article by Sonia Águila et al., published in Molecular Therapy, adding:
“Small regulatory RNAs are getting more and more interest. This manuscript details how a low expression of miR 146a was linked to a genetic variant (rs2431697 T allele carriers), known for influencing innate and adaptative immunity, was also associated with more thrombotic events in cardiovascular disease and increased agonist dependent platelet activation in healthy individuals.
In addition, the rs2431697 T allele was associated with spontaneous platelet activation and a poor clinical outcome in pulmonary inflammatory disease including COVID 19.
So, how does this variant act?
Major clues were obtained from metabolomic studies on miR 146 or mice who had decreased amounts of fatty acid beta oxidation due to a higher expression of an enzyme, Cpt1a (carnitine parmitoyltransferase 1A).
Overriding this higher expression with a Cpt1a inhibitor restored platelet activation to normal levels. Significantly, miR 146 or mice also manifested increased pulmonary occlusion leading to higher mortality in a systemic thrombosis model.
Effects on other blood cells were not excluded. Injection of a miR 146 mimetic protected the mice against thrombosis suggesting it as a possible future antithrombotic therapy in man
This important study again highlights how rare miR SNPs can influence the outcome of major illnesses.
This makes me think that similar studies are needed in my domain rare inherited bleeding disorders where platelet function is diminished and in such disorders as Glanzmann thrombasthenia where patients, even family members, can have the same genetic profile but highly different clinical severity or even, on occasion, unexplained thrombotic causes.
This manuscript from a group of internationally recognized authors is highly recommended.”
Title: miR-146a mimic therapy protects against platelet-mediated thrombosis
Authors: Sonia Águila, Juan C. García Cañaveras, Laura Zapata Martínez, Ana B. Arroyo, Nuria García Barberá, Salvador Carrillo Tornel, Pedro J. Guijarro, Carrillo, Paula González Jiménez, Ana Latorre, María L. Lozano, Bernard Payrastre, José Rivera, Marie Pierre Gratacap, Raúl Méndez, Agustín Lahoz, Marcin Kortylewski, Rocío González Conejero, Constantino Martínez
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