MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

RATIONALE: In the search for markers and modulators of vascular disease, miRNAs have emerged as potent therapeutic targets.

OBJECTIVE: To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke.

METHODS AND RESULTS: Utilizing patient material from the Biobank of Karolinska Endarterectomies (BiKE), we profiled miRNA expression in patients with stable vs unstable carotid plaque. A PCR-based miRNA array of plasma, sampled at the carotid lesion site, identified eight deregulated miRNAs (miR-15b, -29c, -30c/d, -150, -191, -210 and -500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser-capture microdissection as well as in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene adenomatous polyposis coli (APC), thereby affecting Wnt signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in two rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease.

CONCLUSIONS: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.