Abstract 605: Identification of Differential Roles of Microrna-33a and -33b During Atherosclerosis Progression with Genetically Modified Mice

Backgrounds: MicroRNA (miR)-33a targets cholesterol transporter ATP-binding cassette protein A1 or other anti-atherogenic targets and contributes to atherogenesis. Its inhibition or deletion is known to result in the amelioration of atherosclerosis. However, mice lack the other member of miR-33 family, miR-33b, which exists in humans. Thus, precise evaluation and comparison of the responsibilities of these two miRs during the progression of atherosclerosis has not been investigated. Methods and Results: The difference between miR-33a and miR-33b were analyzed from multiple directions using genetically modified mice. We generated four strains with or without miR-33a and miR-33b. Comparison of these strains showed distinct distribution and regulation of miR-33 family. In particular, comparison between mice with only miR-33a (wild-type mice) and mice with only miR-33b (miR-33a -/- /miR-33b +/+ ) revealed the prevalence of miR-33b in the liver. Such differential expression resulted in a worsened serum cholesterol profile in mice with only miR-33b. On the contrary, in macrophages the expression level of miR-33 family genes was similar and their effects on cholesterol efflux capacity were almost comparable. To evaluate the whole body atherogenic potency, we developed ApoE -/- /miR-33a +/+ /miR-33b -/- mice and ApoE -/- /miR-33a -/- /miR-33b +/+ mice. ApoE -/- /miR-33a -/- /miR-33b +/+ mice developed increased atherosclerotic plaque compared with ApoE -/- /miR-33a +/+ /miR-33b -/- mice, in line with the predominant expression of miR-33b in the liver and worsened serum cholesterol profile. On the contrary, a bone marrow transplantation study showed no significant difference, and this was consistent with the relevant expression levels of miR-33a and miR-33b in bone marrow cells. Conclusions: miR-33 family exhibited differences in distribution and regulation, and particularly in the progression of atherosclerosis, miR-33b would be more potent than miR-33a.