MicroRNA

About

Scientists have found miRNA that plays a role in vasclular remodelling, reducing atherosclerotic plaques while stimulating therapeutic angiogenesis. An important problem with therapeutic neovascularization is that stimulation of positive vascular remodelling such as angiogenesis and arteriogenesis often also stimulate negative vascular remodelling such as atherosclerosis and restenosis.  This Janus phenomenon causes obvious problems when developing treatments to stimulate neovascularization in patents with occlusive arterial disease. Researchers  have found that inhibition of a particular microRNA gene cluster plays a role in vascular remodelling.  Inhibitors of select miRNA were tested in vivo in mice on a high fat diet and were demonstrated to reduce atherosclerosis and restenosis with a 50% reduction in plaque size. The inhibitors were also found to greatly stabilize the plaque phenotype since there was a 50% or more decrease in necrotic core formation in the plaque, decrease macrophage content in plaques, and decrease plasma total cholesterol. At the same time, inhibition of these miRNA was unexpectedly found to increase therapeutic angiogenesis as demonstrated in a mouse hind limb ischemia model.  These data indicate a potentially novel regulatory pathway and new target for ischemic cardiovascular disease.  Inhibition of these miRNA’s would, for the first time, provide the opportunity to inhibit atherosclerosis and restenosis while simultaneously stimulating therapeutic neovascularization.  Using cultures of smooth muscle cells, endothelial cells, fibroblasts, bone marrow derived mast cells and macrophages, they were able to confirm direct regulation of multiple anti-atherogenic target genes by microRNAs Inhibition of miRNA leads to: Reduction in plaque size Decrease necrotic core formation in plaques Decrease macrophage content in plaques Decrease plasma total cholesterol Stimulation of therapeutic angiogenesis Applications: Development of therapeutic agent to prevent or treat atherosclerotic plaques while increasing angiogenesis Exploration of miRNA downstream targets