Editors' ChoiceCardiovascular Disease

The Last Line of Defense Against Atherosclerosis

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Science Translational Medicine  19 Mar 2014:
Vol. 6, Issue 228, pp. 228ec51
DOI: 10.1126/scitranslmed.3008868

Atherosclerosis of the blood vessels that feed the brain, heart, and limbs is the leading cause of global morbidity and mortality. Damage to the endothelial lining of arterial blood vessels, which causes the disease, can be triggered by a variety of stressors—metabolic, immune, and oxidative—all of which are highly prevalent in patients at risk for atherosclerosis. Impaired endothelial cells can lead to a dysfunctional endothelium, influx of cholesterol, and promotion of atherosclerotic lesions. To date, cardiologists have few tools in their armamentarium to preserve this vital protective barrier function of the endothelial lining. In work by Schober et al., the authors find a new contributor to atherosclerosis that points to a potential treatment approach to preserve endothelial health.

Because deletion of the gene encoding pre-miR-126 affects vascular integrity, the authors tested the hypothesis that a pre-miR-126 derivative, miR-126-5p, contributes to vascular repair. They crossed mice lacking the pre-miR-126 gene with mice deficient in the APOE gene, which develop hyperlipidemia and atherosclerosis. The offspring showed impaired endothelial recovery after endothelial damage and increased atherosclerotic lesion size. This effect was mediated by an inhibitor of NOTCH1, Dlk1, which is a direct target of miR-126-5p.

In ApoE-deficient mice fed a high-cholesterol diet, miR-126-5p was down-regulated at sites that are predisposed to atherosclerosis (because of turbulent blood flow), leading directly to the development of atherosclerosis through the up-regulation of Dlk. To demonstrate the translational potential of their findings, the authors treated these mice with mimics of miR-126-5p, improving endothelial cell proliferation and reducing atherosclerosis. The authors conclude that mir-126-5p protects against atherosclerosis by maintaining the health of the endothelial lining.

This proof-of-concept study in mouse models lays the foundation for new therapeutics designed around mir-126-5p in humans. Small RNA molecules can be delivered systemically (or locally on the tip of a catheter) to sites of atherosclerosis to mimic (or antagonize) the effects of the miRNA, making this approach feasible. As a consequence, doctors may have a new tool to prevent atherosclerosis.

A. Schober et al., MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat. Med., published online 2 March 2014 (10.1038/nm.3487). [Full Text]

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