mir33 Inhibition Overcomes Deleterious Effects of Diabetes on Atherosclerosis Plaque Regression in Mice
Rationale: Diabetes increases cardiovascular disease risk in humans and remains elevated despite cholesterol-lowering therapy with statins. Consistent with this, in mouse models diabetes impairs atherosclerosis plaque regression after aggressive cholesterol-lowering. miR33 is a key negative regulator of the reverse cholesterol transport factors, ABCA1 and HDL, which suggested that its inhibition may overcome this impairment.
Objective: To assess the effects of miR33 inhibition on atherosclerosis regression in diabetic mice.
Methods and Results: Reversa mice, which are deficient in the LDL receptor and in which hypercholesterolemia is reversed by conditional inactivation of the microsomal triglyceride transfer protein (Mttp) gene, were placed on an atherogenic diet for 16 weeks, then either made diabetic by STZ injection or kept normoglycemic. Lipid-lowering was induced by Mttp inactivation and mice were treated with anti-miR33 or control oligonucleotides. Whereas regression was impaired in diabetic mice treated with control oligonucleotides, anti-miR33 treatment decreased plaque macrophage content and inflammatory gene expression in these mice. The decreased macrophage content in anti-miR33-treated diabetic mice was associated with a blunting of hyperglycemia-induced monocytosis and reduced monocyte recruitment to the plaque, which was traced to an inhibition of the proliferation of bone marrow monocyte precursors associated with the upregulation of their Abca1.
Conclusions: miR33 inhibition overcomes deleterious effects of diabetes in atherosclerosis regression in mice, which suggests a therapeutic strategy in diabetic patients, who remain at elevated cardiovascular disease risk despite plasma cholesterol lowering.
- Received April 14, 2014.
- Revision received September 3, 2014.
- Accepted September 5, 2014.