Inhibitory effect of small interfering RNA targeting peroxisome-proliferator-activated receptor-γcoactivator-1αon retinal neovascularization in the mouse_Chinese Journal of Ocular Fundus Diseases

Authors：

 JiangJian , XiaXiaobo , ZhangLixin

Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, China;

Corresponding author：

JiangJian, Email: jiangjianxy@126.com

Keywords：

Retinal neovascularization/drug therapy; Peroxisome proliferator-activated receptors; RNA Interference; Animal experimentation

DOI：

10.3760/cma.j.issn.1005-1015.2015.03.014

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To evaluate the inhibitory effect of small interfering RNA (siRNA) targeting peroxisome-proliferator-activated receptor-γcoactivator-1α(PGC-1α) on retinal neovascularization in the mouse. Methods Eighty seven-day-old C57BL/6J mice were divided into normal group, model blank group, model control group and PGC-1αsiRNA group, twenty mice in each group. Mice in the normal group were kept in normal room air. Mice in the model blank group, model control group and PGC-1αsiRNA group were induced for retinal neovascularization by hypoxia. Liposome with PGC-1αsiRNA (1 μl) and liposome with negative control siRNA (1 μl) were injected into the vitreous in the PGC-1αsiRNA group and model control group respectively when mice were moved out to room air from the cabin (Postnatal 12). No injection were performed in the model blank group. At postnatal 17, fluorescein angiography was used to assess the vascular pattern.The proliferative neovascular response was quantified by counting the nuclei of new vessels extending from the retina into the vitreous in cross-sections. PGC-1αand vascular endothelial growth factor (VEGF) level in retina were measured by real-time polymerase chain reaction (real-time PCR) and Western blot. Inhibition efficiency of PGC-1αsiRNA on PGC-1αand VEGF was calculated. Results Mice in the normal group showed reticular distribution of retinal blood vessels. Central nonperfused retina, neovascular tufts and fluorescein leakage were seen in the model blank group and model control group. Neovascular tuft and fluorescein leakage were decreased in the PGC-1αsiRNA group compared to the model blank group and model control group. The neovascular nuclei were increased in the model blank group and model control group compared to the normal group (P < 0.05). The neovascular nuclei were decreased in the PGC-1αsiRNA group compared to the model blank group and model control group (P < 0.05). The expression of PGC-1αmRNA and protein in retina was increased significantly in the model blank group and model control group as compared with normal group, while decreased 54% and 53% respectively in the PGC-1αsiRNA group as compared with model blank group and model control group (P < 0.05). The expression of VEGF mRNA and protein in retina was increased significantly in the model blank group and model control group as compared with normal group, while decreased significantly in the PGC-1αsiRNA group (decreased 48% and 40% respectively) as compared with model blank group and model control group (P < 0.05). Conclusions Intravitreal injection of PGC-1αsiRNA mediated by liposome can inhibit retinal neovascularization in the mouse effectively.

Citation： JiangJian, XiaXiaobo, ZhangLixin. Inhibitory effect of small interfering RNA targeting peroxisome-proliferator-activated receptor-γcoactivator-1αon retinal neovascularization in the mouse. Chinese Journal of Ocular Fundus Diseases, 2015, 31(3): 268-273. doi: 10.3760/cma.j.issn.1005-1015.2015.03.014 Copy

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1. Gariano RF, Gardner TW. Retinal angiogenesis in development and disease[J]. Nature, 2005, 438(7070):960-966.
2. Jain RK. Molecular regulation of vessel maturation[J]. Nature Med, 2003, 9(6):685-693.
3. Ferrara N, Gerber HP, LeCounter J. The biology of VEGF and its receptors[J]. Nat Med, 2003, 9(6):669-676.
4. Saint-Geniez M, D'Amore PA. Development and pathology of the hyaloid, choroidal and retinal vasculature[J]. Int J Dev Biol, 2004, 48(8-9):1045-1058.
5. Olsson AK, Dimberg A, Kreuger J, et al. VEGF receptor signaling-in control of vascular function[J]. Nat Rev Mol Cell Bio, 2006, 7(5):359-371.
6. Arany Z, Foo SY, Ma Y, et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α[J]. Nature, 2008, 451(7181):1008-1012.
7. Saint-Geniez M, Jiang A, Abend S, et al. PGC-1αregulates normal and pathological angiogenesis in the retina[J]. Am J Pathol, 2013, 182(1):255-265.
8. Chen J, Michan S, Juan AM, et al. Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy[J]. Angiogenesis, 2013, 16(4):985-992.
9. Smith LE, Wesolowski E, McLellan A, et al.Oxygen-induced retinopathy in the mouse[J]. Invest Ophthalmol Vis Sci, 1994, 35(1):101-110.
10. Barger PM, Browning AC, Garner AN, et al. p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptorα:a potential role in the cardiac metabolic stress response[J]. J Biol Chem, 2001, 276(48):44495-44501.
11. Mascareno E, Manukyan I, Das DK, et al. Downregulation of cardiac lineage protein (CLP-1) expression in CLP-1+/-mice affords cardioprotection against ischemic stress[J]. J Cell Mol Med, 2008, 13(8B):2744-2753.
12. Gutsaeva DR, Carraway MS, Suliman HB, et al. Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism[J]. J Neurosci, 2008, 28(9):2015-2024.
13. Chen SD, Lin TK, Yang DI, et al. Protective effects of peroxisome proliferator-activated receptors gamma coactivator-1 alpha against neuronal cell death in the hippocampal CA1 subfield after transient global ischemia[J]. J Neurosci Res, 2010, 88(3):605-613.
14. Rasbach KA, Schnellmann RG. Signaling of mitochondrial biogenesis following oxidant injury[J]. J Biol Chem, 2007, 282(4):2355-2362.
15. Norrbom J, Sundberg CJ, Ameln H, et al. PGC-1αmRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle[J]. J Appl Physiol, 2004, 96(1):189-194.
16. Stein RA, Gaillard S, McDonnell DP. Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells[J]. J Steroid Biochem Mol Biol, 2009, 114(1-2):106-112.
17. Leick L, Hellsten Y, Fentz J, et al. PGC-1alpha mediates exercise-induced skeletal muscle VEGF expression in mice[J]. Am J Physiol Endocrinol Metab, 2009, 297(1):92-103.
18. Chinsomboon J, Ruas J, Gupta RK, et al. The transcriptional coactivator PGC-1αmediates exercise-induced angiogenesis in skeletal muscle[J]. Proc Natl Acad Sci USA, 2009, 106(50):21401-21406.
19. Carmeliet P, Baes M. Metabolism and therapeutic angiogenesis[J]. N Engl J Med, 2008, 358(23):2511-2512.

Chinese Journal of Ocular Fundus Diseases

Inhibitory effect of small interfering RNA targeting peroxisome-proliferator-activated receptor-γcoactivator-1αon retinal neovascularization in the mouse

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