In order to bring you the best possible user experience, this site uses Javascript. If you are seeing this message, it is likely that the Javascript option in your browser is disabled. For optimal viewing of this site, please ensure that Javascript is enabled for your browser.
Did you know that your browser is out of date? To get the best experience using our website we recommend that you upgrade to a newer version. Learn more.

Noncanonical function of nuclear miR-126-5p sustains endothelial integrity and prevents atherosclerosis

Commented by the ESC WG on Atherosclerosis and Vascular Biology

Comment: MicroRNAs (miRNAs) are versatile regulators of gene expression with profound implications for atherosclerosis, but whether they can exert additional functions to control cell adaptation was unknown. Our study unveiled an unexpected noncanonical function of miR-126-5p that sustain endothelial integrity. Endothelial cells exposed to protective high-shear stress activate the autophagy machinery which facilitate the interaction of miR-126-5p with the RNA-binding protein Mex3a to form a ternary complex with AGO2. This complex forms on the surface of autophagic vesicles to drive its nuclear localization. Once in the nucleus, miR-126-5p dissociates from AGO2 and establishes aptamer-like interactions with the effector caspase-3. The binding to miR-126-5p prevents dimerization and proper active site formation of caspase-3, thus inhibiting proteolytic activity and limiting apoptosis. Disrupting this pathway in vivo by genetic deletion of Mex3a or by specific deficiency of endothelial autophagy aggravates endothelial apoptosis and exacerbates atherosclerosis. Taken together, our findings reveal an important pathway composed of sequential miRNA-protein interaction which preserve endothelial integrity. Although further studies will be required, we foresee a potential therapeutic relevance in modulating this pathway to prevent endothelial dysfunction in atherosclerosis and in conditions where viability of the endothelium is crucial for a cardiovascular outcome (e.g. reendothelialization following angioplasty).

Noncanonical function of nuclear miR-126-5p.png

Figure legend. Summary of the MEX3A-guided nuclear miR-126-5p pathway. (1) Atheroprotective high shear stress (HSS), activation of KLF2 (Kruppel like factor 2), and mTORC-inhibition by rapamycin favors the assembly of a ternary complex of miR-126-5p with Mex3a and AGO2. (2) This complex localizes on the extraluminal surface of autophagosome, which preserves it from degradation and leads to its nuclear transfer. (3) In the nucleus, miR-126-5p dissociates from AGO2 and Mex3a and becomes available for binding the effector caspase, caspase-3 (CASP3), which can be transferred to the nucleus when activated.



Santovito D, Egea V, Weber C. Small but smart: MicroRNAs orchestrate
atherosclerosis development and progression. Biochim Biophys Acta. 2016
Dec;1861(12 Pt B):2075-2086.

Peters LJF, Biessen EAL, Hohl M, Weber C, van der Vorst EPC, Santovito D.
Small Things Matter: Relevance of MicroRNAs in Cardiovascular Disease. Front Physiol. 2020 Jul 7;11:793.

Schober A, Nazari-Jahantigh M, Wei Y, Bidzhekov K, Gremse F, Grommes J,
Megens RT, Heyll K, Noels H, Hristov M, Wang S, Kiessling F, Olson EN, Weber C. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med. 2014 Apr;20(4):368-76.

Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, Hristov M, Köppel T, Jahantigh MN, Lutgens E, Wang S, Olson EN, Schober A, Weber C. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal. 2009 Dec 8;2(100):ra81.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

Contact us

ESC Working Group on Atherosclerosis & Vascular Biology

European Society of Cardiology

European Heart House
Les Templiers
2035 Route des Colles
CS 80179 Biot

06903, Sophia Antipolis, FR

Tel: +