Suppression of retinal neovascularization by small interfering RNA targeting PGC-1α

Zhang,Lixin; Jiang,Jian; Xia,Xiaobo

doi:10.3892/ijmm.2014.1717

Suppression of retinal neovascularization by small interfering RNA targeting PGC-1α

Authors:
- Lixin Zhang
- Jian Jiang
- Xiaobo Xia
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Affiliations: Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: March 31, 2014 https://doi.org/10.3892/ijmm.2014.1717
Pages: 1523-1530

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Abstract

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key coordinator of gene programs in metabolism and energy homeostasis in mammals. The aim of this study was to determine whether PGC-1α is involved in the transcriptional regulation of retinal neovascularization in oxygen-induced retinopathy (OIR). The expression of PGC-1α in the retina of mice with OIR was detected by real-time polymerase chain reaction (PCR) and western blot analysis. Mice with OIR were administered small interfering RNA (siRNA) targeting PGC-1α by intravitreal injection, and the effects of PGC-1α siRNA were confirmed by fluorescein angiography and quantification of pre-retinal neovascular nuclei in the retinal sections. PGC-1α was upregulated at both the mRNA and protein level under hypoxic conditions. Retinal neovascularization was inhibited by PGC-1α siRNA. Furthermore, PGC-1α mRNA and protein levels were also reduced by PGC-1α siRNA, which were detected by real-time PCR and western blot analysis. The downregulation of PGC-1α expression resulted in the reduction of vascular endothelial growth factor (VEGF) expression in the mice. In conclusion, siRNA targeting PGC-1α inhibits retinal neovascularization by downregulating the expression of PGC-1α and VEGF in the murine retina. Therefore, PGC-1α represents a potential therapeutic target for ischemia-induced retinal diseases and other ocular neovascular diseases.

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1	Al-Latayfeh M, Silva PS, Sun JK and Aiello LP: Antiangiogenic therapy for ischemic retinopathies. Cold Spring Harb Perspect Med. 2:a0064112012. View Article : Google Scholar : PubMed/NCBI
2	Watanabe D, Suzuma K, Matsui S, Kurimoto M, Kiryu J, Kita M, Suzuma I, Ohashi H, Ojima T, Murakami T, Kobayashi T, Masuda S, Nagao M, Yoshimura N and Takagi H: Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med. 353:782–792. 2005. View Article : Google Scholar : PubMed/NCBI
3	Pe’er J, Shweiki D, Itin A, Hemo I, Gnessin H and Keshet E: Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Invest. 72:638–645. 1995.PubMed/NCBI
4	Aiello LP, Northrup JM, Keyt BA, Takagi H and Iwamoto MA: Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol. 113:1538–1544. 1995. View Article : Google Scholar : PubMed/NCBI
5	Sondell M, Sundler F and Kanje M: Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci. 12:4243–4254. 2000. View Article : Google Scholar : PubMed/NCBI
6	Rosenfeld PJ, Rich RM and Lalwani GA: Ranibizumab: Phase III clinical trial results. Ophthalmol Clin North Am. 19:361–372. 2006.PubMed/NCBI
7	Xia XB, Xiong SQ, Xu HZ, Jiang J and Li Y: Suppression of retinal neovascularization by shRNA targeting HIF-1alpha. Curr Eye Res. 33:892–902. 2008. View Article : Google Scholar : PubMed/NCBI
8	Xiong SQ, Xia XB, Xu HZ and Jiang J: Suppression of retinal neovascularization by small-interference RNA targeting erythropoietin. Ophthalmologica. 223:306–312. 2009. View Article : Google Scholar : PubMed/NCBI
9	Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J, Rangwala SM, Baek KH, Rosenzweig A and Spiegelman BM: HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 451:1008–1012. 2008. View Article : Google Scholar : PubMed/NCBI
10	Saint-Geniez M, Jiang A, Abend S, Liu L, Sweigard H, Connor KM and Arany Z: PGC-1α regulates normal and pathological angiogenesis in the retina. Am J Pathol. 182:255–265. 2013.
11	Puigserver P, Wu Z, Park CW, Graves R, Wright M and Spiegelman BM: A cold-Iducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 92:829–839. 1998. View Article : Google Scholar : PubMed/NCBI
12	Larrouy D, Vidal H, Andreelli F, Laville M and Langin D: Cloning and mRNA tissue distribution of human PPARgamma coactivator-1. Int J Obes Relat Metab Disord. 23:1327–1332. 1999. View Article : Google Scholar : PubMed/NCBI
13	Valle I, Alvarez-Barrientos A, Arza E, Lamas S and Monsalve M: PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res. 66:562–573. 2005. View Article : Google Scholar : PubMed/NCBI
14	Borniquel S, Valle I, Cadenas S, Lamas S and Monsalve M: Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC-1alpha. FASEB J. 20:1889–1991. 2006. View Article : Google Scholar : PubMed/NCBI
15	Barger PM, Browning AC, Garner AN and Kelly DP: p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. J Biol Chem. 276:44495–44501. 2001. View Article : Google Scholar
16	Mascareno E, Manukyan I, Das DK and Siddiqui MA: Down-regulation of cardiac lineage protein (CLP-1) expression in CLP-1 +/− mice affords. J Cell Mol Med. 13:2744–2753. 2009.
17	Gutsaeva DR, Carraway MS, Suliman HB, Demchenko IT, Shitara H, Yonekawa H and Piantadosi CA: Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. J Neurosci. 28:2015–2024. 2008. View Article : Google Scholar
18	Chen SD, Lin TK, Yang DI, Lee SY, Shaw FZ, Liou CW and Chuang YC: Protective effects of peroxisome proliferator-activated receptors gamma coactivator-1alpha against neuronal cell death in the hippocampal CA1 subfield after transient global ischemia. J Neurosci Res. 88:605–613. 2010.
19	Rasbach KA and Schnellmann RG: Signaling of mitochondrial biogenesis following oxidant injury. J Biol Chem. 282:2355–2362. 2007. View Article : Google Scholar : PubMed/NCBI
20	Norrbom J, Sunderg CJ, Ameln H, Kraus WE, Jansson E and Gustafsson T: PGC-1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol (1985). 96:189–194. 2004. View Article : Google Scholar : PubMed/NCBI
21	Stein RA, Gallard S and McDonnell DP: Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells. J Steroid Biochem Mol Biol. 114:106–112. 2009. View Article : Google Scholar : PubMed/NCBI
22	Carmeliet P and Baes M: Metabolism and therapeutic angiogenesis. N Engl J Med. 358:2511–2512. 2008. View Article : Google Scholar : PubMed/NCBI
23	Elbashir SM, Lendeckel W and Tuschl T: RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev. 15:188–200. 2001. View Article : Google Scholar : PubMed/NCBI
24	Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R and D’Amore PA: Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci. 35:101–111. 1994.PubMed/NCBI
25	Banin E, Dorrell MI, Aguilar E, Ritter MR, Aderman CM, Smith AC, Friedlander J and Friedlander M: T2-TrpRS inhibits preretinal neovascularization and enhances physiological vascular regrowth in OIR as assessed by a new method of quantification. Invest Ophthalmol Vis Sci. 47:2125–2134. 2006. View Article : Google Scholar
26	Gebarowska D, Stitt AW, Gardiner TA, Harriott P, Greer B and Nelson J: Synthetic peptides interacting with the 67-kd laminin receptor can reduce retinal ischemia and inhibit hypoxia-induced retinal neovascularization. Am J Pathol. 160:307–313. 2002. View Article : Google Scholar
27	Abbas-Terki, Blanco-Bose W, Déglon N, Pralong W and Aebischer P: Lentiviral- mediated RNA interference. Hum Gene Ther. 13:2197–2201. 2002. View Article : Google Scholar : PubMed/NCBI
28	Chin L, Hahn WC, Getz G and Meyerson M: Making sense of cancer genomic data. Genes Dev. 25:534–555. 2011. View Article : Google Scholar
29	Zhang T, Zhou Q and Pignoni F: Yki/YAP, Sd/TEAD and Hth/MEIS control tissue specification in the Drosophila eye disc epithelium. PLoS One. 6:e222782011. View Article : Google Scholar : PubMed/NCBI
30	Cooper TA, Wan L and Dreyfuss G: RNA and disease. Cell. 136:777–793. 2009. View Article : Google Scholar
31	Olejniczak M, Galka P and Krzyzosiak WJ: Sequence-non-specific effects of RNA interference triggers and microRNA regulators. Nucleic Acids Res. 38:1–16. 2010. View Article : Google Scholar : PubMed/NCBI
32	Shen J, Samul R, Silva RL, et al: Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther. 13:225–234. 2006. View Article : Google Scholar : PubMed/NCBI
33	Lipardi C, Wei Q and Paterson BM: RNAi as random degradative PCR: siRNA primers convert mRNA into dsRNAs that are degraded to generate new siRNAs. Cell. 107:297–307. 2001. View Article : Google Scholar : PubMed/NCBI
34	Arjamaa O and Nikinmaa M: Oxygen-dependent diseases in the retina: Role of hypoxia- inducible factors. Exp Eye Res. 83:473–483. 2006. View Article : Google Scholar : PubMed/NCBI
35	Afzal A, Shaw LC, Ljubimov AV, Boulton ME, Segal MS and Grant MB: Retinal and choroidal microangiopathies: therapeutic opportunities. Microvasc Res. 74:131–144. 2007. View Article : Google Scholar : PubMed/NCBI
36	Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD and Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16:4604–4613. 1996.PubMed/NCBI
37	Fraisl P, Baes M and Carmeliet P: Hungry for blood vessels: linking metabolism and angiogenesis. Dev Cell. 14:313–314. 2008. View Article : Google Scholar : PubMed/NCBI