- 期刊
- OpenAccess
【論文摘要】The Identification of Differential Roles of Microrna-33a and -33b During Atherosclerosis Progression with Genetically Modified Mice
摘要
Background: MicroRNA (miR)-33 targets cholesterol transporter ATP-binding cassette protein A1 or other anti-atherogenic targets and contributes to atherogenic progression. Its inhibition or deletion is known to result in the amelioration of atherosclerosis in mice. However, mice lack the other member of miR-33 family, miR-33b, which exists in humans and other large mammals. Thus, precise evaluation and comparison of the responsibilities of these two miRs during the progression of atherosclerosis has not been investigated, although they are essential. Methods and Results: In this study, we analyzed the difference between miR-33a and miR-33b from multiple directions using genetically modified mice. We generated four strains with or without miR-33a and miR-33b. The comparison of these strains revealed the distinct distribution and regulation of miR-33 family. The 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. To evaluate the whole body atherogenic potency of miR-33a and miR-33b, we developed Apolipoprotein E-deficient (ApoE-/-)/miR- 33a+/+/miR-33b-/- mice and ApoE-/-/miR-33a-/-/miR-33b+/+ mice. With a high-fat and high-cholesterol diet, 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: The 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.