Dataset Information

Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis.

ABSTRACT: As an important regulator of macrophage cholesterol efflux and HDL biogenesis, miR-33 is a promising target for treatment of atherosclerosis, and numerous studies demonstrate that inhibition of miR-33 increases HDL levels and reduces plaque burden. However, important questions remain about how miR-33 impacts atherogenesis, including whether this protection is primarily due to direct effects on plaque macrophages or regulation of lipid metabolism in the liver. We demonstrate that miR-33 deficiency in Ldlr-/- mice promotes obesity, insulin resistance, and hyperlipidemia but does not impact plaque development. We further assess how loss of miR-33 or addition of miR-33b in macrophages and other hematopoietic cells impact atherogenesis. Macrophage-specific loss of miR-33 decreases lipid accumulation and inflammation under hyperlipidemic conditions, leading to reduced plaque burden. Therefore, the pro-atherogenic effects observed in miR-33-deficient mice are likely counterbalanced by protective effects in macrophages, which may be the primary mechanism through which anti-miR-33 therapies reduce atherosclerosis.

SUBMITTER: Price NL

PROVIDER: S-EPMC5687841 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis.

Price Nathan L NL Rotllan Noemi N Canfrán-Duque Alberto A Zhang Xinbo X Pati Paramita P Arias Noemi N Moen Jack J Mayr Manuel M Ford David A DA Baldán Ángel Á Suárez Yajaira Y Fernández-Hernando Carlos C

Cell reports 20171001 5

As an important regulator of macrophage cholesterol efflux and HDL biogenesis, miR-33 is a promising target for treatment of atherosclerosis, and numerous studies demonstrate that inhibition of miR-33 increases HDL levels and reduces plaque burden. However, important questions remain about how miR-33 impacts atherogenesis, including whether this protection is primarily due to direct effects on plaque macrophages or regulation of lipid metabolism in the liver. We demonstrate that miR-33 deficienc ...[more]

PMID: 29091769

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Project description:Background Gastric cancer (GC) is a major cancer-related mortality disease. Gambogic acid (GA) has been investigated to inhibit cancer progression. In the present study, the molecular mechanism of GA in regulating GC progression was studied. Methods The expression levels of circular RNA ASAP2 (circ_ASAP2), miR-33a-5p and cyclin-dependent kinases 7 (CDK7) were detected by quantitative real-time polymerase reaction (qRT-PCR). CDK7 protein level was evaluated by Western blot. Cell colony formation assay, 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, transwell assay and flow cytometry analysis were employed to reveal the functional effects among circ_ASAP2, miR-33a-5p and CDK7 on GA-induced GC progression. Mechanistically, the binding relationship between miR-33a-5p and circ_ASAP2 or CDK7 was predicted with starBase v3.0 online database and verified by dual-luciferase reporter assay. In vivo tumor formation assay was used to explain the impacts of GA treatment on GC growth in vivo. Results Circ_ASAP2 and CDK7 expression were downregulated in GA-induced GC cells compared with GC cells. MiR-33a-5p expression was upregulated in GA-induced GC cells relative to GC cells. The protein expression level of CDK7 was lower in GA-induced GC cells than that in GC cells. Further, circ_ASAP2 overexpression decreased GA-induced inhibition effects on cell proliferation, migration and invasion and GA-induced promotion effect on cell apoptosis in both AGS and HGC-27 cells, whereas this phenomenon was reversed by miR-33a-5p. In addition, circ_ASAP2 functioned as a sponge of miR-33a-5p and miR-33a-5p was associated with CDK7. Furthermore, GA treatment inhibited GC growth in vivo. Conclusion Circ_ASAP2 overexpression promoted cell proliferation, migration and invasion, whereas inhibited cell apoptosis by upregulating CDK7 expression through binding to miR-33a-5p in GA-induced GC cells. This study provided a theoretical basis in GC treatment with GA.

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Dataset Information

Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis.

Publications

Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis.

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