Open Access

MicroRNA‑93 regulates angiogenesis in peripheral arterial disease by targeting CDKN1A

  • Authors:
    • Xiaojun Shu
    • Youjun Mao
    • Zhengfei Li
    • Wenhui Wang
    • Yaowen Chang
    • Shengye Liu
    • Xiao‑Qiang Li
  • View Affiliations

  • Published online on: April 25, 2019     https://doi.org/10.3892/mmr.2019.10196
  • Pages: 5195-5202
  • Copyright: © Shu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

MicroRNAs (miRNAs) are considered to be critical mediators of gene expression with respect to tumor progression, although their role in ischemia‑induced angiogenesis is poorly characterized, including in peripheral arterial disease (PAD). Furthermore, the underlying mechanism of action of specific miRNAs in PAD remains unknown. Reverse transcription‑quantitative polymerase chain reaction analysis revealed that microRNA‑93 (miR‑93) was significantly upregulated in patients with PAD and in the EA.hy926 endothelial cells in response to hypoxia. Additionally, miRNA (miR)‑93 promoted angiogenesis by enhancing proliferation, migration and tube formation. Cyclin dependent kinase inhibitor 1A (CDKN1A), verified as a potential target gene of miR‑93, was inhibited by overexpressed miR‑93 at the protein and mRNA expression levels. Furthermore, a hind‑limb ischemia model served to evaluate the role of miR‑93 in angiogenesis in vivo, and the results demonstrated that miR‑93 overexpression enhanced capillary density and perfusion recovery from hind‑limb ischemia. Taken together, miR‑93 was indicated to be a promising target for pharmacological regulation to promote angiogenesis, and the miR‑93/CDKN1A pathway may function as a novel therapeutic approach in PAD.

References

1 

Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Faraci FM, Malinow MR and Heistad DD: Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest. 98:24–29. 1996. View Article : Google Scholar : PubMed/NCBI

2 

Tawakol A, Omland T, Gerhard M, Wu JT and Creager MA: Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation. 95:1119–1121. 1997. View Article : Google Scholar : PubMed/NCBI

3 

Faxon DP, Fuster V, Libby P, Beckman JA, Hiatt WR, Thompson RW, Topper JN, Annex BH, Rundback JH, Fabunmi RP, et al: Atherosclerotic vascular disease conference: Writing group III: Pathophysiology. Circulation. 109:2617–2625. 2004. View Article : Google Scholar : PubMed/NCBI

4 

Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S and Goodman D: The prevalence of peripheral arterial disease in a defined population. Circulation. 71:510–515. 1985. View Article : Google Scholar : PubMed/NCBI

5 

Selvin E and Erlinger TP: Prevalence of and risk factors for peripheral arterial disease in the United States: Results from the National health and nutrition examination survey, 1999–2000. Circulation. 110:738–743. 2004. View Article : Google Scholar : PubMed/NCBI

6 

Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; TASC II Working Group, ; Bell K, Caporusso J, Durand-Zaleski I, et al: Inter-society consensus for the management of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg. 33 (Suppl 1):S1–S75. 2007. View Article : Google Scholar : PubMed/NCBI

7 

Morisaki K, Yamaoka T and Iwasa K: Risk factors for wound complications and 30-day mortality after major lower limb amputations in patients with peripheral arterial disease. Vascular. 26:12–17. 2018. View Article : Google Scholar : PubMed/NCBI

8 

Weragoda J, Seneviratne R, Weerasinghe MC and Wijeyaratne SM: Risk factors of peripheral arterial disease: A case control study in Sri Lanka. BMC Res Notes. 9:5082016. View Article : Google Scholar : PubMed/NCBI

9 

Forés R, Alzamora MT, Pera G, Valverde M, Angla M, Baena-Díez JM and Mundet-Tuduri X: Evolution and degree of control of cardiovascular risk factors after 5 years of follow-up and their relationship with the incidence of peripheral arterial disease: ARTPER cohort. Med Clin (Barc). 148:107–113. 2017.(In English, Spanish). View Article : Google Scholar : PubMed/NCBI

10 

Trionfini P and Benigni A: MicroRNAs as master regulators of glomerular function in health and disease. J Am Soc Nephrol. 28:1686–1696. 2017. View Article : Google Scholar : PubMed/NCBI

11 

Kato M and Natarajan R: MicroRNAs in diabetic nephropathy: Functions, biomarkers, and therapeutic targets. Ann N Y Acad Sci. 1353:72–88. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Stather PW, Sylvius N, Wild JB, Choke E, Sayers RD and Bown MJ: Differential microRNA expression profiles in peripheral arterial disease. Circ Cardiovasc Genet. 6:490–497. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, Weber M, Hamm CW, Röxe T, Müller-Ardogan M, et al: Circulating microRNAs in patients with coronary artery disease. Circ Res. 107:677–684. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Savita U and Karunagaran D: MicroRNA-106b-25 cluster targets β-TRCP2, increases the expression of Snail and enhances cell migration and invasion in H1299 (non small cell lung cancer) cells. Biochem Biophys Res Commun. 434:841–847. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Fang L, Deng Z, Shatseva T, Yang J, Peng C, Du WW, Yee AJ, Ang LC, He C, Shan SW and Yang BB: MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-β8. Oncogene. 30:806–821. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Fang L, Du WW, Yang W, Rutnam ZJ, Peng C, Li H, O'Malley YQ, Askeland RW, Sugg S, Liu M, et al: MiR-93 enhances angiogenesis and metastasis by targeting LATS2. Cell Cycle. 11:4352–4365. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Liu S, Patel SH, Ginestier C, Ibarra I, Martin-Trevino R, Bai S, McDermott SP, Shang L, Ke J, Ou SJ, et al: MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLoS Genet. 8:e10027512012. View Article : Google Scholar : PubMed/NCBI

18 

Li F, Liang X, Chen Y, Li S and Liu J: Role of microRNA-93 in regulation of angiogenesis. Tumour Biol. 35:10609–10613. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Xu YF, Mao YP, Li YQ, Ren XY, He QM, Tang XR, Sun Y, Liu N and Ma J: MicroRNA-93 promotes cell growth and invasion in nasopharyngeal carcinoma by targeting disabled homolog-2. Cancer Lett. 363:146–155. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Liu G, Friggeri A, Yang Y, Park YJ, Tsuruta Y and Abraham E: miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proc Natl Acad Sci USA. 106:15819–15824. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Yang F, Huang XR, Chung AC, Hou CC, Lai KN and Lan HY: Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition. J Pathol. 221:390–401. 2010.PubMed/NCBI

22 

Koka V, Huang XR, Chung AC, Wang W, Truong LD and Lan HY: Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am J Pathol. 172:1174–1183. 2008. View Article : Google Scholar : PubMed/NCBI

23 

Sun Q, Chen RR, Shen Y, Mooney DJ, Rajagopalan S and Grossman PM: Sustained vascular endothelial growth factor delivery enhances angiogenesis and perfusion in ischemic hind limb. Pharm Res. 22:1110–1116. 2005. View Article : Google Scholar : PubMed/NCBI

24 

Ge Y, Sun Y and Chen J: IGF-II is regulated by microRNA-125b in skeletal myogenesis. J Cell Biol. 192:69–81. 2011. View Article : Google Scholar : PubMed/NCBI

25 

Couffinhal T, Silver M, Zheng LP, Kearney M, Witzenbichler B and Isner JM: Mouse model of angiogenesis. Am J Pathol. 152:1667–1679. 1998.PubMed/NCBI

26 

Bao H, Lv F and Liu T: A pro-angiogenic degradable Mg-poly(lactic-co-glycolic acid) implant combined with rhbFGF in a rat limb ischemia model. Acta Biomaterial. 64:279–289. 2017. View Article : Google Scholar

27 

McDermott MM, Greenland P, Liu K, Guralnik JM, Celic L, Criqui MH, Chan C, Martin GJ, Schneider J, Pearce WH, et al: The ankle brachial index is associated with leg function and physical activity: The walking and leg circulation study. Ann Intern Med. 136:873–883. 2002. View Article : Google Scholar : PubMed/NCBI

28 

Mcdermott MG, Liu K, Jack M, Guralnik MD, Mehta S, Criqui MH, Martin GJ and Greenland P: The ankle brachial index independently predicts walking velocity and walking endurance in peripheral arterial disease. J Am Geriatr Soc. 46:1355–1362. 1998. View Article : Google Scholar : PubMed/NCBI

29 

McDermott MM, Liu K, Greenland P, Guralnik JM, Criqui MH, Chan C, Pearce WH, Schneider JR, Ferrucci L, Celic L, et al: Functional decline in peripheral arterial disease: Associations with the ankle brachial index and leg symptoms. JAMA. 292:453–461. 2004. View Article : Google Scholar : PubMed/NCBI

30 

Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI

31 

John B, Enright AJ, Aravin A, Tuschl T, Sander C and Marks DS: Correction: Human MicroRNA targets. PLoS Biol. 2:e3632004. View Article : Google Scholar : PubMed/NCBI

32 

Hazarika S, Farber CR, Dokun AO, Pitsillides AN, Wang T, Lye RJ and Annex BH: MicroRNA-93 controls perfusion recovery following hind-limb ischemia by modulating expression of multiple genes in the cell cycle pathway. Circulation. 127:1818–1828. 2013. View Article : Google Scholar : PubMed/NCBI

33 

Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Huang Q, Gumireddy K, Schrier M, le Sage C, Nagel R, Nair S, Egan DA, Li A, Huang G, Klein-Szanto AJ, et al: The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol. 10:202–210. 2008. View Article : Google Scholar : PubMed/NCBI

35 

Slovut DP and Sullivan TM: Critical limb ischemia: Medical and surgical management. Vasc Med. 13:281–291. 2008. View Article : Google Scholar : PubMed/NCBI

36 

Liu Z, Yang D, Xie P, Ren G, Sun G, Zeng X and Sun X: MiR-106b and MiR-15b modulate apoptosis and angiogenesis in myocardial infarction. Cell Physiol Biochem. 29:851–862. 2012. View Article : Google Scholar : PubMed/NCBI

37 

Kuehbacher A, Urbich C, Zeiher AM and Dimmeler S: Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res. 101:59–68. 2007. View Article : Google Scholar : PubMed/NCBI

38 

Chamorro-Jorganes A, Araldi E, Penalva LO, Sandhu D, Fernández-Hernando C and Suárez Y: MicroRNA-16 and microRNA-424 regulate cell-autonomous angiogenic functions in endothelial cells via targeting vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1. Arterioscler Thromb Vasc Biol. 31:2595–2606. 2011. View Article : Google Scholar : PubMed/NCBI

39 

Dokun AO, Keum S, Hazarika S, Li Y, Lamonte GM, Wheeler F, Marchuk DA and Annex BH: A quantitative trait locus (LSq-1) on mouse chromosome 7 is linked to the absence of tissue loss after surgical hindlimb ischemia. Circulation. 117:1207–1215. 2008. View Article : Google Scholar : PubMed/NCBI

40 

Chalothorn D, Clayton JA, Zhang H, Pomp D and Faber JE: Collateral density, remodeling and VEGF-A expression differ widely between mouse strains. Physiol Genomics. 30:179–191. 2007. View Article : Google Scholar : PubMed/NCBI

41 

Long J, Wang Y, Wang W, Chang BH and Danesh FR: Identification of microRNA-93 as a novel regulator of vascular endothelial growth factor in hyperglycemic conditions. J Biol Chem. 285:23457–23465. 2010. View Article : Google Scholar : PubMed/NCBI

42 

Negishi M, Wongpalee S P, Sarkar S, Park J, Lee KY, Shibata Y, Reon BJ, Abounader R, Suzuki Y, Sugano S and Dutta A: A new lncRNA, APTR, associates with and represses the CDKN1A/p21 promoter by recruiting polycomb proteins. PLoS One. 9:e952162014. View Article : Google Scholar : PubMed/NCBI

43 

Nuntharatanapong N, Chen K, Sinhaseni P and Keaney JF Jr: EGF receptor-dependent JNK activation is involved in arsenite-induced p21Cip1/Waf1 upregulation and endothelial apoptosis. Am J Physiol Heart Circ Physiol. 289:H99–H107. 2005. View Article : Google Scholar : PubMed/NCBI

44 

Yamagata K, Suzuki S and Tagami M: Docosahexaenoic acid prevented tumor necrosis factor alpha-induced endothelial dysfunction and senescence. Prostaglandins Leukot Essent Fatty Acids. 104:11–18. 2016. View Article : Google Scholar : PubMed/NCBI

45 

Yin DX, Zhao HM, Sun DJ, Yao J and Ding DY: Identification of candidate target genes for human peripheral arterial disease using weighted gene co-expression network analysis. Mol Med Rep. 12:8107–8112. 2015. View Article : Google Scholar : PubMed/NCBI

46 

Spinetti G, Cordella D, Fortunato O, Sangalli E, Losa S, Gotti A, Carnelli F, Rosa F, Riboldi S, Sessa F, et al: Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients: Implication of the microRNA-155/FOXO3a signaling pathway. Circ Res. 11:510–522. 2013. View Article : Google Scholar

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June 2019
Volume 19 Issue 6

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Copy and paste a formatted citation
APA
Shu, X., Mao, Y., Li, Z., Wang, W., Chang, Y., Liu, S., & Li, X. (2019). MicroRNA‑93 regulates angiogenesis in peripheral arterial disease by targeting CDKN1A. Molecular Medicine Reports, 19, 5195-5202. https://doi.org/10.3892/mmr.2019.10196
MLA
Shu, X., Mao, Y., Li, Z., Wang, W., Chang, Y., Liu, S., Li, X."MicroRNA‑93 regulates angiogenesis in peripheral arterial disease by targeting CDKN1A". Molecular Medicine Reports 19.6 (2019): 5195-5202.
Chicago
Shu, X., Mao, Y., Li, Z., Wang, W., Chang, Y., Liu, S., Li, X."MicroRNA‑93 regulates angiogenesis in peripheral arterial disease by targeting CDKN1A". Molecular Medicine Reports 19, no. 6 (2019): 5195-5202. https://doi.org/10.3892/mmr.2019.10196