Abstract 127: Induction of miR-21 Increases Fibrous Cap Stability in Vulnerable Atherosclerotic Lesions

The aim of the present study was to explore the role of miRNAs as potential regulators in patients with carotid artery stenosis and concordant vulnerable atherosclerotic plaques. A pre-determined miRNA-array of laser captured micro-dissected (LCM) tissue specimen from fibrous caps of 10 symptomatic patients (stroke or TIA within > 14 days and histo-morphologically identified ruptured lesion) compared to fibrous caps from 10 asymptomatic patients (stable lesions; high grade stenosis) discovered miR-21 as one of the two miRNAs (miRs-21 and -210) being substantially down-regulated in symptomatic patients. To functionally evaluate the contribution of miR-21 to plaque vulnerability, we created miR21 -/- / ApoE -/- mice on a C57BL/6 background. We explored the phenotype of these newly developed miR21 -/- /ApoE -/- mice in experimental models of vascular remodelling and plaque vulnerability. First, miR21 -/- mice revealed a complete lack of SMC proliferation in response to carotid ligation injury. In the second inducible plaque rupture model, using incomplete ligation of the common carotid artery with consecutive cuff placement proximal to the ligated region indicated that all miR21 -/- /ApoE -/- mice ( n =10) presented atherothombotic events and signs of severe plaque instability. The rupture rate in control miR21 +/+ /ApoE -/- mice was significantly lower at 56% ( n =9). In addition, miR21 -/- /ApoE -/- showed an increase in lesion area in the aortic root and substantially higher levels of macrophage infiltration in injured carotid arteries. Dynamic live cell imaging, using isolated aortic SMCs and peritoneal macrophages from miR21 -/- /ApoE -/- vs. miR2 +/+ /ApoE -/- mice displayed substantial lower cellular proliferation and survival rates (for SMCs), and distinct advanced inflammatory activity upon oxidized LDL (oxLDL) stimulation of macrophages. In the present study we identified miR-21 as a key modulator of pathologic processes in atherosclerosis-related vascular remodelling. Targeted, lesion-site specific overexpression of miR-21 could be a novel and powerful future strategy to stabilize vulnerable plaques by inducing pro-proliferative mechanisms in SMC-enriched fibrous caps.