MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

Abstract

Stroke is the second most common cause of death 2 and major cause of disability worldwide, 2 with survivors often depending on lifelong care. Carotid stenosis is the second most common predecessor of ischemic stroke, 3 and carotid endarterectomy (CEA; and to a lesser extent carotid artery stenting) are accepted as secondary, but also primary preventive therapy. 2,4,5 With new imaging techniques, vulnerable plaques at risk of rupture can be identified with increasing accuracy, 6 but in the majority of cases, the perioperative surgical risk of ≈3% still outweighs the risk of plaque rupture in asymptomatic carotid stenosis carriers.7 As a result, CEA and carotid artery stenting are currently unfavorable for most of these individuals.8 Detection and stabilization of a vulnerable plaque by influencing the local disease process biologically would provide a sophisticated solution for asymptomatic plaque carriers at risk of stroke. Molecular Medicine© 2016 American Heart Association, Inc. 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.

MicroRNAs as Harbingers of High-Risk Carotid Artery Atherosclerotic Disease?

“…Although Raitoharju et al 4 showed that miR-210 expression (along with several other miRNAs) was increased in atherosclerotic plaques compared to non-atherosclerotic left internal thoracic arteries, the strength of the current study from Eken et al 3 lies in categorizing patients into symptomatic and asymptomatic subgroups and the use of plasma in combination with laser-capture microdissection (LCM) of isolated tissues. The advantage of analyzing LCM-derived tissue may explain this new finding of reduced miR-210 expression in ruptured fibrous caps by Eken et al 3 since in their hands, analysis of total carotid arterial tissue did not reveal any differences in symptomatic vs asymptomatic lesions. Consistent with these findings, miR-210 expression was reduced, as shown by in situ hybridization (ISH), specifically in ruptured fibrous caps compared to stable plaques after partial carotid artery ligation in mice.…”

“…In this context, the study from Eken et. al 3 provides a strong foundation for understanding the pathophysiological mediators of these unstable atherosclerotic carotid lesions by profiling microRNAs (miRNAs) in plasma sampled at the carotid lesion site in patients with stable or unstable carotid plaques at the time of surgical CEA.…”

Increased Carotid Artery Lesion Inflammation Upon Treatment With the CD137 Agonistic Antibody 2A

“…19 Forty-three male Apoe −/− mice were bought from Taconic (Taconic Europe A/S, Denmark). Four of the 43 mice died during the experimental atherothrombosis induction.…”

“…17, 19 Thombosis frequency was evaluated by visual inspection of the lesion area and IHC, supplemented by immunohistochemical analysis when required. The atherothrombosis frequency was lower in 2A-compared to IgG2a-treated mice, but there was no significant difference between groups ( Figure 3G).…”

“…Next, 12-week-old Apoe −/− mice were subjected to carotid artery ligation 17, 19 and treated with weekly injections of 2A or control IgG2a until euthanasia at 16 weeks of age (Figure 1). There was no significant difference in weight development between 2A-and IgG2a-treated mice over the experimental period (data not shown).…”