Abstract 11544: MicroRNA-145 Targeted Therapy Reduces Atherosclerosis and Improves Plaque Stability
MicroRNAs are essential post-transcriptional modulators of gene expression that coordinate and integrate multiple regulatory pathways, and have been implicated in various chronic diseases. Since microRNA-145 is highly expressed in vascular smooth muscle cells (VSMCs) and regulates VSMC fate and plasticity, we hypothesized that it may be a novel regulator of atherosclerosis and plaque stability. Atherosclerosis-proneApoE-/- mice were treated with either microRNA-145 lentivirus under the control of the smooth muscle cell-specific promoter SM22α ορ ΣΜ22α χοντρολ λεντιvιρυσ βεfορε χομμενχινγ τηε Ωεστερν διετ fορ 12 ωεεκσ. MicroRNA-145 treatment markedly reduced plaque sizes in aortic sinuses, ascending aortas and brachiocephalic arteries. MicroRNA-145 therapy also significantly increased fibrous cap area, reduced the necrotic core area/total plaque area ratio, elevated plaque collagen content, and attenuated MMP-2 and MMP-9 activity. The macrophage content of in plaque areas was significantly decreased in microRNA-145-treated ApoE-/- mice. To determine if microRNA-145 lentivirus therapy would alter lesion characteristics and accumulation of contractile (vs. synthetic) VSMC in atherosclerotic plaques, we stained cross sections of brachiocephalic arteries for the VSMC marker proteins, α-SMA and calponin. MicroRNA-145-treated ApoE-/- mice exhibited a marked increase in α-SMA-positive SMC area in their atherosclerotic lesions and these areas were also positive for calponin. We evaluated the effects of microRNA-145 on myocardin and KLF4, two well established targets that mediate the effects of microRNA-145 and found increased myocardin and reduced KLF4 expressions in aortas from microRNA-145-treated ApoE-/- mice, consistent with an effect of microRNA-145 to promote a contractile phenotype of VSMCs. In summary, microRNA-145 is a novel therapeutic target to limit atherosclerotic plaque morphology, and cellular composition shifting the balance towards plaque stability vs. plaque rupture. These benefits appear to be mediated through an effect of microRNA-145 to promote VSMC differentiation towards the contractile phenotype, via a mechanism that involves reciprocal regulation of myocardin and KLF4.
- © 2011 by American Heart Association, Inc.