Therapeutic manipulation of angiogenesis with miR-27b

Vascular Cell

Olga V. Volpert⁴  Raj Kishore³  Alexander Roy Mackie⁵  Sol Misener²  Gangjian Qin⁵  Dauren Biyashev⁵  Dorina Veliceasa¹ 

[1] Department of Urology, University of Illinois at Chicago Medical College, Chicago, IL, USA;Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA;Northwestern University, Feinberg Cardiovascular Research Institute, Chicago, IL, USA;Department of Medicine, Cardiology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

关键词: Cancer;    Cardiovascular;    Ischemia;    Therapeutic angiogenesis;    miR-27b;    miRNA;   

Others  :  1220764
DOI  :  10.1186/s13221-015-0031-1

 received in 2015-03-30, accepted in 2015-06-08,  发布年份 2015

【 摘 要 】

Background

Multiple studies demonstrated pro-angiogenic effects of microRNA (miR)-27b. Its targets include Notch ligand Dll4, Sprouty (Spry)-2, PPARγ and Semaphorin (SEMA) 6A. miR-27 effects in the heart are context-dependent: although it is necessary for ventricular maturation, targeted overexpression in cardiomyocytes causes hypertrophy and dysfunction during development. Despite significant recent advances, therapeutic potential of miR-27b in cardiovascular disease and its effects in adult heart remain unexplored. Here, we assessed the therapeutic potential of miR-27b mimics and inhibitors in rodent models of ischemic disease and cancer.

Methods

We have used a number of models to demonstrate the effects of miR-27b mimicry and inhibition in vivo, including subcutaneous Matrigel plug assay, mouse models of hind limb ischemia and myocardial infarction and subcutaneous Lewis Lung carcinoma.

Results

Using mouse model of myocardial infarction due to the coronary artery ligation, we showed that miR-27b mimic had overall beneficial effects, including increased vascularization, decreased fibrosis and increased ejection fraction. In mouse model of critical limb ischemia, miR-27b mimic also improved tissue re-vascularization and perfusion. In both models, miR-27b mimic clearly decreased macrophage recruitment to the site of hypoxic injury. In contrast, miR-27b increased the recruitment of bone marrow derived cells to the neovasculature, as was shown using mice reconstituted with fluorescence-tagged bone marrow. These effects were due, at least in part, to the decreased expression of Dll4, PPARγ and IL10. In contrast, blocking miR-27b significantly decreased vascularization and reduced growth of subcutaneous tumors and decreased BMDCs recruitment to the tumor vasculature.

Conclusions

Our study demonstrates the utility of manipulating miR-27b levels in the treatment of cardiovascular disease and cancer.

【 授权许可】

   
2015 Veliceasa et al.

【 图 表 】

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【 参考文献 】

• [1]Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000; 407(6801):249-57.
• [2]Carmeliet P. Manipulating angiogenesis in medicine. J Intern Med. 2004; 255(5):538-61.
• [3]Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005; 438(7070):967-74.
• [4]Mousa SA, Mousa SS. Current status of vascular endothelial growth factor inhibition in age-related macular degeneration. BioDrugs. 2010; 24(3):183-94.
• [5]Syrigos KN, Karapanagiotou E, Boura P, Manegold C, Harrington K. Bevacizumab-induced hypertension: pathogenesis and management. BioDrugs. 2011; 25(3):159-69.
• [6]Peng L, Zhao Q, Ye X, Zhou Y, Hu D, Zheng S. Incidence and risk of proteinuria with aflibercept in cancer patients: a meta-analysis. PloS one. 2014; 9(11):
• [7]Keefe D, Bowen J, Gibson R, Tan T, Okera M, Stringer A. Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. Oncologist. 2011; 16(4):432-44.
• [8]Elice F, Rodeghiero F. Bleeding complications of antiangiogenic therapy: pathogenetic mechanisms and clinical impact. Thromb Res. 2010; 125 Suppl 2:S55-7.
• [9]Otsu S, Hirashima Y, Nishikawa K, Sakashita H, Morinaga R, Watanabe K et al.. Neurological toxicity in metastatic colorectal cancer patients treated with modified FOLFOX6 Plus Bevacizumab. Jpn Clin Med. 2014; 5:19-23.
• [10]Grenon NN. Managing toxicities associated with antiangiogenic biologic agents in combination with chemotherapy for metastatic colorectal cancer. Clin J Oncol Nurs. 2013; 17(4):425-33.
• [11]Smart N, Dube KN, Riley PR. Coronary vessel development and insight towards neovascular therapy. Int J Exp Pathol. 2009; 90(3):262-83.
• [12]Yla-Herttuala S. An update on angiogenic gene therapy: vascular endothelial growth factor and other directions. Curr Opin Mol Ther. 2006; 8(4):295-300.
• [13]Grochot-Przeczek A, Dulak J, Jozkowicz A. Therapeutic angiogenesis for revascularization in peripheral artery disease. Gene. 2013; 525(2):220-8.
• [14]Lavu M, Gundewar S, Lefer DJ. Gene therapy for ischemic heart disease. J Mol Cell Cardiol. 2011; 50(5):742-50.
• [15]Jin H, Wyss JM, Yang R, Schwall R. The therapeutic potential of hepatocyte growth factor for myocardial infarction and heart failure. Curr Pharm Des. 2004; 10(20):2525-33.
• [16]Hammer A, Steiner S. Gene therapy for therapeutic angiogenesis in peripheral arterial disease–a systematic review and meta-analysis of randomized, controlled trials. VASA. 2013; 42(5):331-9.
• [17]Annex BH. Therapeutic angiogenesis for critical limb ischaemia. Nat Rev Cardiol. 2013; 10(7):387-96.
• [18]Gupta NK, Armstrong EJ, Parikh SA. The current state of stem cell therapy for peripheral artery disease. Curr Cardiol Rep. 2014; 16(2):447.
• [19]Tongers J, Losordo DW, Landmesser U. Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties, and challenges. Eur Heart J. 2011; 32(10):1197-206.
• [20]Westenskow PD, Kurihara T, Aguilar E, Scheppke EL, Moreno SK, Wittgrove C et al.. Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting. J Clin Invest. 2013; 123(11):4900-8.
• [21]Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA et al.. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008; 15(2):261-71.
• [22]Lu Y, Heng X, Yu J, Su Q, Guan X, You C et al.. miR-137 regulates the migration of human umbilical vein endothelial cells by targeting ephrin-type A receptor 7. Mol Med Rep. 2014; 10(3):1475-80.
• [23]Kane NM, Howard L, Descamps B, Meloni M, McClure J, Lu R et al.. Role of microRNAs 99b, 181a, and 181b in the differentiation of human embryonic stem cells to vascular endothelial cells. Stem Cells. 2012; 30(4):643-54.
• [24]He T, Qi F, Jia L, Wang S, Song N, Guo L et al.. MicroRNA-542-3p inhibits tumour angiogenesis by targeting angiopoietin-2. J Pathol. 2014; 232(5):499-508.
• [25]Wang S, Olson EN. AngiomiRs–key regulators of angiogenesis. Curr Opin Genet Dev. 2009; 19(3):205-11.
• [26]Biyashev D, Veliceasa D, Topczewski J, Topczewska JM, Mizgirev I, Vinokour E et al.. miR-27b controls venous specification and tip cell fate. Blood. 2012; 119:2679-87.
• [27]Urbich C, Kaluza D, Fromel T, Knau A, Bennewitz K, Boon RA et al.. MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A. Blood. 2012; 119(6):1607-16.
• [28]Zhou Q, Gallagher R, Ufret-Vincenty R, Li X, Olson EN, Wang S. Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23 ~ 27 ~ 24 clusters. Proc Natl Acad Sci U S A. 2011; 108(20):8287-92.
• [29]Passaniti A, Taylor RM, Pili R, Guo Y, Long PV, Haney JA et al.. A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab Invest. 1992; 67((4):519-28.
• [30]Niiyama H, Huang NF, Rollins MD, Cooke JP. Murine model of hindlimb ischemia. JoVE. 2009;23. Epub 2009/02/21.
• [31]Limbourg A, Korff T, Napp LC, Schaper W, Drexler H, Limbourg FP. Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia. Nat Protoc. 2009; 4(12):1737-46.
• [32]Iwakura A, Shastry S, Luedemann C, Hamada H, Kawamoto A, Kishore R et al.. Estradiol enhances recovery after myocardial infarction by augmenting incorporation of bone marrow-derived endothelial progenitor cells into sites of ischemia-induced neovascularization via endothelial nitric oxide synthase-mediated activation of matrix metalloproteinase-9. Circulation. 2006; 113(12):1605-14.
• [33]Isner JM, Kalka C, Kawamoto A, Asahara T. Bone marrow as a source of endothelial cells for natural and iatrogenic vascular repair. Ann N Y Acad Sci. 2001; 953:75-84.
• [34]Qi W, Yang C, Dai Z, Che D, Feng J, Mao Y et al.. High levels of pigment epithelium-derived factor in diabetes impair wound healing through suppression of Wnt signaling. Diabetes. 2015; 64(4):1407-19.
• [35]Tung JJ, Tattersall IW, Kitajewski J. Tips, stalks, tubes: notch-mediated cell fate determination and mechanisms of tubulogenesis during angiogenesis. Cold Spring Harbor perspectives in medicine. 2012;2(2):a006601. Epub 2012/02/23.
• [36]Xu F, Zhang X, Lei Y, Liu X, Liu Z, Tong T et al.. Loss of repression of HuR translation by miR-16 may be responsible for the elevation of HuR in human breast carcinoma. J Cell Biochem. 2010; 111(3):727-34.
• [37]Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W. Stress-induced reversal of microRNA repression and mRNA P-body localization in human cells. Cold Spring Harb Symp Quant Biol. 2006; 71:513-21.
• [38]Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell. 2006; 125(6):1111-24.
• [39]Jennewein C, von Knethen A, Schmid T, Brune B. MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA destabilization. J Biol Chem. 2010; 285(16):11846-53.
• [40]Gacche RN, Meshram RJ. Angiogenic factors as potential drug target: efficacy and limitations of anti-angiogenic therapy. Biochim Biophys Acta. 2014; 1846(1):161-79.
• [41]Codina M, Elser J, Margulies KB. Current status of stem cell therapy in heart failure. Curr Cardiol Rep. 2010; 12(3):199-208.
• [42]Ouma GO, Rodriguez E, Muthumani K, Weiner DB, Wilensky RL, Mohler ER. In vivo electroporation of constitutively expressed HIF-1alpha plasmid DNA improves neovascularization in a mouse model of limb ischemia. J Vasc Surg . 2014; 59(3):786-93.
• [43]Yla-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J. Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol. 2007; 49(10):1015-26.
• [44]Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011; 469(7330):336-42.
• [45]van Rooij E, Marshall WS, Olson EN. Toward microRNA-based therapeutics for heart disease: the sense in antisense. Circ Res. 2008; 103(9):919-28.
• [46]Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res. 2008; 79(4):581-8.
• [47]Chen WJ, Yin K, Zhao GJ, Fu YC, Tang CK. The magic and mystery of microRNA-27 in atherosclerosis. Atherosclerosis. 2012; 222(2):314-23.
• [48]Chinchilla A, Lozano E, Daimi H, Esteban FJ, Crist C, Aranega AE et al.. MicroRNA profiling during mouse ventricular maturation: a role for miR-27 modulating Mef2c expression. Cardiovasc Res. 2011; 89(1):98-108.
• [49]Busk PK, Cirera S. MicroRNA profiling in early hypertrophic growth of the left ventricle in rats. Biochem Biophys Res Commun. 2010; 396(4):989-93.
• [50]Jentzsch C, Leierseder S, Loyer X, Flohrschutz I, Sassi Y, Hartmann D et al.. A phenotypic screen to identify hypertrophy-modulating microRNAs in primary cardiomyocytes. J Mol Cell Cardiol. 2012; 52(1):13-20.
• [51]Wang J, Song Y, Zhang Y, Xiao H, Sun Q, Hou N et al.. Cardiomyocyte overexpression of miR-27b induces cardiac hypertrophy and dysfunction in mice. Cell Res. 2012; 22(3):516-27.
• [52]Graham JR, Williams CM, Yang Z. MicroRNA-27b targets gremlin 1 to modulate fibrotic responses in pulmonary cells. J Cell Biochem. 2014; 115(9):1539-48.
• [53]Zhang M, Wu JF, Chen WJ, Tang SL, Mo ZC, Tang YY et al.. MicroRNA-27a/b regulates cellular cholesterol efflux, influx and esterification/hydrolysis in THP-1 macrophages. Atherosclerosis. 2014; 234(1):54-64.
• [54]Vickers KC, Shoucri BM, Levin MG, Wu H, Pearson DS, Osei-Hwedieh D et al.. MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia. Hepatology. 2013; 57(2):533-42.
• [55]Kang T, Lu W, Xu W, Anderson L, Bacanamwo M, Thompson W et al.. MicroRNA-27 (miR-27) targets prohibitin and impairs adipocyte differentiation and mitochondrial function in human adipose-derived stem cells. J Biol Chem. 2013; 288(48):34394-402.
• [56]Karbiener M, Fischer C, Nowitsch S, Opriessnig P, Papak C, Ailhaud G et al.. microRNA miR-27b impairs human adipocyte differentiation and targets PPARgamma. Biochem Biophys Res Commun. 2009; 390((2):247-51.
• [57]Bang C, Fiedler J, Thum T. Cardiovascular importance of the microRNA-23/27/24 family. Microcirculation. 2012; 19(3):208-14.
• [58]Wang JM, Tao J, Chen DD, Cai JJ, Irani K, Wang Q et al.. MicroRNA miR-27b rescues bone marrow-derived angiogenic cell function and accelerates wound healing in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2014; 34(1):99-109.
• [59]Peric D, Chvalova K, Rousselet G. Identification of microprocessor-dependent cancer cells allows screening for growth-sustaining micro-RNAs. Oncogene. 2012; 31(16):2039-48.
• [60]Shen S, Sun Q, Liang Z, Cui X, Ren X, Chen H et al.. A prognostic model of triple-negative breast cancer based on miR-27b-3p and node status. PLoS One. 2014; 9(6):
• [61]Ishteiwy RA, Ward TM, Dykxhoorn DM, Burnstein KL. The microRNA -23b/-27b cluster suppresses the metastatic phenotype of castration-resistant prostate cancer cells. PLoS One. 2012; 7(12):
• [62]Jin L, Wessely O, Marcusson EG, Ivan C, Calin GA, Alahari SK. Prooncogenic factors miR-23b and miR-27b are regulated by Her2/Neu, EGF, and TNF-alpha in breast cancer. Cancer Res. 2013; 73(9):2884-96.
• [63]Ali S, Banerjee S, Logna F, Bao B, Philip PA, Korc M et al.. Inactivation of Ink4a/Arf leads to deregulated expression of miRNAs in K-Ras transgenic mouse model of pancreatic cancer. J Cell Physiol. 2012; 227(10):3373-80.
• [64]Alt EU, Senst C, Murthy SN, Slakey DP, Dupin CL, Chaffin AE et al.. Aging alters tissue resident mesenchymal stem cell properties. Stem Cell Res. 2012; 8(2):215-25.
• [65]Chiyomaru T, Seki N, Inoguchi S, Ishihara T, Mataki H, Matsushita R et al.. Dual regulation of receptor tyrosine kinase genes EGFR and c-Met by the tumor-suppressive microRNA-23b/27b cluster in bladder cancer. Int J Oncol. 2015; 46(2):487-96.
• [66]Kjersem JB, Ikdahl T, Lingjaerde OC, Guren T, Tveit KM, Kure EH. Plasma microRNAs predicting clinical outcome in metastatic colorectal cancer patients receiving first-line oxaliplatin-based treatment. Mol Oncol. 2014; 8(1):59-67.
• [67]Thulasingam S, Massilamany C, Gangaplara A, Dai H, Yarbaeva S, Subramaniam S et al.. miR-27b*, an oxidative stress-responsive microRNA modulates nuclear factor-kB pathway in RAW 264.7 cells. Mol Cell Biochem. 2011; 352(1–2):181-8.
• [68]Vimalraj S, Selvamurugan N. MicroRNAs: synthesis, gene regulation and osteoblast differentiation. Curr Issues Mol Biol. 2012; 15(1):7-18.