Macrophage miR-34a Is a Key Regulator of Cholesterol Efflux and Atherosclerosis
atherosclerosis; inflammation; cholesterol efflux; ABCA1; ABCG1; LXR; miR-34a
Macrophages play a crucial role in the pathogenesis of atherosclerosis, but the molecular mechanisms remain poorly understood. Here we show that microRNA-34a (miR-34a) is a key regulator of macrophage cholesterol efflux and reverse cholesterol transport by modulating ATP-binding cassette transporters ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1). miR-34a also regulates M1 and M2 macrophage polarization via liver X receptor α. Furthermore, global loss of miR-34a reduces intestinal cholesterol or fat absorption by inhibiting cytochrome P450 enzymes CYP7A1 and sterol 12α-hydroxylase (CYP8B1). Consistent with these findings, macrophage-selective or global ablation of miR-34a markedly inhibits the development of atherosclerosis. Finally, therapeutic inhibition of miR-34a promotes atherosclerosis regression and reverses diet-induced metabolic disorders. Our studies outline a central role of miR-34a in regulating macrophage cholesterol efflux, inflammation, and atherosclerosis, suggesting that miR-34a is a promising target for treatment of cardiometabolic diseases.
Xu Yanyong; Xu Yang; Zhu Yingdong; Sun Huihui; Juguilon Cody; Li Feng; Fan Daping; Yin Liya; Zhang Yanqiao
Molecular Therapy
2019
2019-01-01
Journal Article
<a href="http://doi.org/10.1016/j.ymthe.2019.09.008" target="_blank" rel="noreferrer noopener">10.1016/j.ymthe.2019.09.008</a>
Specific And Efficient Transduction Of Cochlear Inner Hair Cells With Recombinant Adeno-associated Virus Type 3 Vector
adeno-associated virus; adenovirus; Biotechnology & Applied Microbiology; cochlea; ear; Experimental Medicine; gene transfer; gene transfer; generation; Genetics & Heredity; guinea-pig cochlea; hair cells; in-vivo; promoter; rat; Research &; serotype; therapy; transgene expression
Recombinant adeno-associated virus (AAV) vectors are of interest for cochlear gene therapy because of their ability to mediate the efficient transfer and long-term stable expression of therapeutic genes in a wide variety of postmitotic tissues with minimal vector-related cytotoxicity. In the present study, seven AAV serotypes (AAV1-5, 7, 8) were used to construct vectors. The expression of EGFP by the chicken P-actin promoter associated with the cytomegalovirus immediate-early enhancer in cochlear cells showed that each of these serotypes successfully targets distinct cochlear cell types. In contrast to the other serotypes, the AAV3 vector specifically transduced cochlear inner hair cells with high efficiency in vivo, while the AAV1, 2, 5, 7, and 8 vectors also transduced these and other cell types, including spiral ganglion and spiral ligament cells. There was no loss of cochlear function with respect to evoked auditory brain-stem responses over the range of frequencies tested after the injection of AAV vectors. These findings are of value for further molecular studies of cochlear inner hair cells and for gene replacement strategies to correct recessive genetic hearing loss due to monogenic mutations in these cells.
Liu Y H; Okada T; Sheykholeslami K; Shimazaki K; Nomoto T; Muramatsu S I; Kanazawa T; Takeuchi K; Ajalli R; Mizukami H; Kume A; Ichimura K; Ozawa K
Molecular Therapy
2005
2005-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.ymthe.2005.03.021" target="_blank" rel="noreferrer noopener">10.1016/j.ymthe.2005.03.021</a>
Stromal Cell-Derived Factor-1 Non-Viral DNA Therapy Accelerates Wound Healing and Decreases Scar Formation in Porcine Surgical Incisions
Biotechnology & Applied Microbiology; Genetics & Heredity; Experimental Medicine; Research &
Miller T J; Henson K; Aras R; Facher E; Penn M S
Molecular Therapy
2013
2013-06
Journal Article or Conference Abstract Publication
n/a
Cornoary Sinus Delivery of SDF-1 Plasmid Improves Cardiac Function in a Porcine Model of Heart Failure
Biotechnology & Applied Microbiology; Experimental Medicine; Genetics & Heredity; Research &
Woda J M; Fisher S J; Pastore J; Aras R; Patel A; Penn M S
Molecular Therapy
2014
2014-05
Journal Article
n/a