Login Register Cart 0
Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

MiR-199a-5p Deficiency Promotes Artery Restenosis in Peripheral Artery Disease by Regulating ASMCs Function via Targeting HIF-1α and E2F3

Author(s): Duan Liu, Yexiang Jing, Guiyan Peng, Litai Wei, Liang Zheng, Guangqi Chang* and Mian Wang*

Volume 22, Issue 5, 2024

Published on: 21 June, 2024

Page: [342 - 354] Pages: 13

DOI: 10.2174/0115701611280634240616062413

Price: $65

conference banner
Abstract

Background: Restenosis (RS) poses a significant concern, leading to recurrent ischemia and the potential for amputation following intraluminal angioplasty in the treatment of Peripheral Artery Disease (PAD). Through microRNA microarray analysis, the study detected a significant downregulation of miR-199a-5p within arterial smooth muscle cells (ASMCs) associated with RS.

Objective: This research aims to explore the possible function and the underlying mechanisms of miR-199a-5p in the context of RS.

Methods: Primary ASMCs were extracted from the femoral arteries of both healthy individuals and patients with PAD or RS. The expression levels of miR-199a-5p were assessed using both qRT-PCR and in situ hybridization techniques. To examine the impacts of miR-199a-5p, a series of experiments were performed, including flow cytometry, TUNEL assay, EdU assay, CCK8 assay, Transwell assay, and wound closure assay. A rat carotid balloon injury model was employed to elucidate the mechanism through which miR-199a-5p mitigated neointimal hyperplasia.

Results: MiR-199a-5p exhibited downregulation in RS patients and was predominantly expressed within ASMCs. Elevated the expression of miR-199a-5p resulted in an inhibitory effect of proliferation and migration in ASMCs. Immunohistochemistry and a dual-luciferase reporter assay uncovered that RS exhibited elevated expression levels of both HIF-1α and E2F3, and they were identified as target genes regulated by miR-199a-5p. The co-transfection of lentiviruses carrying HIF-1α and E2F3 alongside miR-199a-5p further elucidated their role in the cellular responses mediated by miR-199a-5p. In vivo, the delivery of miR-199a-5p via lentivirus led to the mitigation of neointimal formation following angioplasty, achieved by targeting HIF-1α and E2F3.

Conclusion: MiR-199a-5p exhibits promise as a prospective therapeutic target for RS since it alleviates the condition by inhibiting the proliferation and migration of ASMCs via its regulation of HIF-1α and E2F3.

Keywords: Peripheral Artery Disease, Restenosis, Arterial Smooth Muscle Cells, miR-199a-5p, HIF-1α, E2F3.

« Previous Next »
Graphical Abstract

[1]
Barnes JA, Eid MA, Creager MA, Goodney PP. Epidemiology and risk of amputation in patients with diabetes mellitus and peripheral artery disease. Arterioscler Thromb Vasc Biol 2020; 40(8): 1808-17.
[http://dx.doi.org/10.1161/ATVBAHA.120.314595] [PMID: 32580632]
[2]
Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg 2007; 33(1): S1-S75.
[http://dx.doi.org/10.1016/j.ejvs.2006.09.024] [PMID: 17140820]
[3]
Smolderen KG, Pacheco C, Provance J, et al. Treatment decisions for patients with peripheral artery disease and symptoms of claudication: Development process and alpha testing of the show-me PAD decision aid. Vasc Med 2021; 26(3): 273-80.
[http://dx.doi.org/10.1177/1358863X20988780] [PMID: 33627058]
[4]
Müller AM, Räpple V, Bradaric C, et al. Outcomes of endovascular treatment for infrapopliteal peripheral artery disease based on the updated TASC II classification. Vasc Med 2021; 26(1): 18-25.
[http://dx.doi.org/10.1177/1358863X20967091] [PMID: 33256573]
[5]
Varma P, Stineman MG, Dillingham TR. Epidemiology of limb loss. Phys Med Rehabil Clin N Am 2014; 25(1): 1-8.
[http://dx.doi.org/10.1016/j.pmr.2013.09.001] [PMID: 24287235]
[6]
Wu BJ, Li Y, Ong KL, et al. Reduction of in-stent restenosis by cholesteryl ester transfer protein inhibition. Arterioscler Thromb Vasc Biol 2017; 37(12): 2333-41.
[http://dx.doi.org/10.1161/ATVBAHA.117.310051] [PMID: 29025709]
[7]
Choe N, Kwon DH, Shin S, et al. The micro RNAmiR-124 inhibits vascular smooth muscle cell proliferation by targeting S100 calcium-binding protein A4 (S100A4). FEBS Lett 2017; 591(7): 1041-52.
[http://dx.doi.org/10.1002/1873-3468.12606] [PMID: 28235243]
[8]
Nakazawa G. Stent thrombosis of drug eluting stent: Pathological perspective. J Cardiol 2011; 58(2): 84-91.
[http://dx.doi.org/10.1016/j.jjcc.2011.07.004] [PMID: 21839616]
[9]
Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: A systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2018; 7(24): e011245.
[http://dx.doi.org/10.1161/JAHA.118.011245] [PMID: 30561254]
[10]
He X, Zheng Y, Liu S, Liu Y, He Y, Zhou X. Altered plasma microRNAs as novel biomarkers for arteriosclerosis obliterans. J Atheroscler Thromb 2016; 23(2): 196-206.
[http://dx.doi.org/10.5551/jat.30775] [PMID: 26370316]
[11]
Loyer X, Potteaux S, Vion AC, et al. Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ Res 2014; 114(3): 434-43.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.302213] [PMID: 24255059]
[12]
Iaconetti C, De Rosa S, Polimeni A, et al. Down-regulation of miR-23b induces phenotypic switching of vascular smooth muscle cells in vitro and in vivo. Cardiovasc Res 2015; 107(4): 522-33.
[http://dx.doi.org/10.1093/cvr/cvv141] [PMID: 25994172]
[13]
Nappi F, Avtaar Singh SS, Jitendra V, Alzamil A, Schoell T. The roles of microRNAs in the cardiovascular system. Int J Mol Sci 2023; 24(18): 14277.
[http://dx.doi.org/10.3390/ijms241814277] [PMID: 37762578]
[14]
Zhang CY, Hu YC, Zhang Y, et al. Glutamine switches vascular smooth muscle cells to synthetic phenotype through inhibiting miR-143 expression and upregulating THY1 expression. Life Sci 2021; 277: 119365.
[http://dx.doi.org/10.1016/j.lfs.2021.119365] [PMID: 33741416]
[15]
Guo X, Li D, Chen M, et al. miRNA-145 inhibits VSMC proliferation by targeting CD40. Sci Rep 2016; 6(1): 35302.
[http://dx.doi.org/10.1038/srep35302] [PMID: 27731400]
[16]
Kmiotek-Wasylewska K, Łabędź-Masłowska A, Bobis-Wozowicz S, et al. Induced pluripotent stem cell-derived extracellular vesicles enriched with miR-126 induce proangiogenic properties and promote repair of ischemic tissue. FASEB J 2024; 38(2): e23415.
[http://dx.doi.org/10.1096/fj.202301836R] [PMID: 38243682]
[17]
Bazan HA, Hatfield SA, O’Malley CB, Brooks AJ, Lightell D Jr, Woods TC. Acute loss of miR-221 and miR-222 in the atherosclerotic plaque shoulder accompanies plaque rupture. Stroke 2015; 46(11): 3285-7.
[http://dx.doi.org/10.1161/STROKEAHA.115.010567] [PMID: 26451018]
[18]
Wang M, Li W, Chang GQ, et al. MicroRNA-21 regulates vascular smooth muscle cell function via targeting tropomyosin 1 in arteriosclerosis obliterans of lower extremities. Arterioscler Thromb Vasc Biol 2011; 31(9): 2044-53.
[http://dx.doi.org/10.1161/ATVBAHA.111.229559] [PMID: 21817107]
[19]
Hu W, Wang M, Yin H, et al. MicroRNA-1298 is regulated by DNA methylation and affects vascular smooth muscle cell function by targeting connexin 43. Cardiovasc Res 2015; 107(4): 534-45.
[http://dx.doi.org/10.1093/cvr/cvv160] [PMID: 26025955]
[20]
Yang F, Chen Q, He S, et al. MiR-22 is a novel mediator of vascular smooth muscle cell phenotypic modulation and neointima formation. Circulation 2018; 137(17): 1824-41.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027799] [PMID: 29246895]
[21]
Dong H, Zhang X, Duan Y, et al. Hypoxia inducible factor-1α regulates microglial innate immune memory and the pathology of Parkinson’s disease. J Neuroinflammation 2024; 21(1): 80.
[http://dx.doi.org/10.1186/s12974-024-03070-2] [PMID: 38555419]
[22]
Imanishi M, Tomita S, Ishizawa K, et al. Smooth muscle cell-specific Hif-1α deficiency suppresses angiotensin II-induced vascular remodelling in mice. Cardiovasc Res 2014; 102(3): 460-8.
[http://dx.doi.org/10.1093/cvr/cvu061] [PMID: 24623277]
[23]
Chang EI, Loh SA, Ceradini DJ, et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation 2007; 116(24): 2818-29.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.715847] [PMID: 18040029]
[24]
Rey S, Lee K, Wang CJ, et al. Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia. Proc Natl Acad Sci USA 2009; 106(48): 20399-404.
[http://dx.doi.org/10.1073/pnas.0911921106] [PMID: 19948968]
[25]
Liang W, Chen J, Zheng H, et al. MiR-199a-5p-containing macrophage-derived extracellular vesicles inhibit SMARCA4 and alleviate atherosclerosis by reducing endothelial cell pyroptosis. Cell Biol Toxicol 2023; 39(3): 591-605.
[http://dx.doi.org/10.1007/s10565-022-09732-2] [PMID: 35930100]
[26]
Malgor RD, Alalahdab F, Elraiyah TA, et al. A systematic review of treatment of intermittent claudication in the lower extremities. J Vasc Surg 2015; 61(3) (Suppl.): 54S-73S.
[http://dx.doi.org/10.1016/j.jvs.2014.12.007] [PMID: 25721067]
[27]
Reinecke H, Unrath M, Freisinger E, et al. Peripheral arterial disease and critical limb ischaemia: Still poor outcomes and lack of guideline adherence. Eur Heart J 2015; 36(15): 932-8.
[http://dx.doi.org/10.1093/eurheartj/ehv006] [PMID: 25650396]
[28]
Feinberg MW, Moore KJ. MicroRNA regulation of atherosclerosis. Circ Res 2016; 118(4): 703-20.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306300] [PMID: 26892968]
[29]
Cheng Y, Liu X, Yang J, et al. MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res 2009; 105(2): 158-66.
[http://dx.doi.org/10.1161/CIRCRESAHA.109.197517] [PMID: 19542014]
[30]
Tang S, Wang F, Shao M, Wang Y, Zhu H. MicroRNA-126 suppresses inflammation in endothelial cells under hyperglycemic condition by targeting HMGB1. Vascul Pharmacol 2017; 88: 48-55.
[http://dx.doi.org/10.1016/j.vph.2016.12.002] [PMID: 27993686]
[31]
Santovito D, Mandolini C, Marcantonio P, et al. Overexpression of microRNA-145 in atherosclerotic plaques from hypertensive patients. Expert Opin Ther Targets 2013; 17(3): 217-23.
[http://dx.doi.org/10.1517/14728222.2013.745512] [PMID: 23339529]
[32]
Liu Y, Liu G, Zhang H, Wang J. MiRNA-199a-5p influences pulmonary artery hypertension via downregulating Smad3. Biochem Biophys Res Commun 2016; 473(4): 859-66.
[http://dx.doi.org/10.1016/j.bbrc.2016.03.140] [PMID: 27038547]
[33]
Hassan T, Carroll TP, Buckley PG, et al. MiR-199a-5p silencing regulates the unfolded protein response in chronic obstructive pulmonary disease and α1-antitrypsin deficiency. Am J Respir Crit Care Med 2014; 189(3): 263-73.
[http://dx.doi.org/10.1164/rccm.201306-1151OC] [PMID: 24299514]
[34]
Hua Q, Jin M, Mi B, et al. LINC01123, a c-Myc-activated long non-coding RNA, promotes proliferation and aerobic glycolysis of non-small cell lung cancer through miR-199a-5p/c-Myc axis. J Hematol Oncol 2019; 12(1): 91.
[http://dx.doi.org/10.1186/s13045-019-0773-y] [PMID: 31488218]
[35]
Cao Y, Cao Z, Wang W, Jie X, Li L. MicroRNA‑199a‑5p regulates FOXC2 to control human vascular smooth muscle cell phenotypic switch. Mol Med Rep 2021; 24(3): 627.
[http://dx.doi.org/10.3892/mmr.2021.12266] [PMID: 34212977]
[36]
Wang G, Li Y, Li J, et al. MicroRNA-199a-5p suppresses glioma progression by inhibiting MAGT1. J Cell Biochem 2019; 120(9): 15248-54.
[http://dx.doi.org/10.1002/jcb.28791] [PMID: 31038761]
[37]
Zeng J, Chen L, Chen B, et al. MicroRNA-199a-5p regulates the proliferation of pulmonary microvascular endothelial cells in hepatopulmonary syndrome. Cell Physiol Biochem 2015; 37(4): 1289-300.
[http://dx.doi.org/10.1159/000430252] [PMID: 26430741]
[38]
Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res 2016; 118(4): 692-702.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306361] [PMID: 26892967]
[39]
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995; 92(12): 5510-4.
[http://dx.doi.org/10.1073/pnas.92.12.5510] [PMID: 7539918]
[40]
Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 2010; 29(5): 625-34.
[http://dx.doi.org/10.1038/onc.2009.441] [PMID: 19946328]
[41]
Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer 2016; 138(5): 1058-66.
[http://dx.doi.org/10.1002/ijc.29519] [PMID: 25784597]
[42]
Akhtar S, Hartmann P, Karshovska E, et al. Endothelial hypoxia-inducible factor-1α promotes atherosclerosis and monocyte recruitment by upregulating MicroRNA-19a. Hypertension 2015; 66(6): 1220-6.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05886] [PMID: 26483345]
[43]
Ben-Shoshan J, Afek A, Maysel-Auslender S, et al. HIF-1alpha overexpression and experimental murine atherosclerosis. Arterioscler Thromb Vasc Biol 2009; 29(5): 665-70.
[http://dx.doi.org/10.1161/ATVBAHA.108.183319] [PMID: 19251587]
[44]
Aarup A, Pedersen TX, Junker N, et al. Hypoxia-inducible factor-1α expression in macrophages promotes development of atherosclerosis. Arterioscler Thromb Vasc Biol 2016; 36(9): 1782-90.
[http://dx.doi.org/10.1161/ATVBAHA.116.307830] [PMID: 27444197]
[45]
Gao Y, Feng B, Lu L, et al. MiRNAs and E2F3: A complex network of reciprocal regulations in human cancers. Oncotarget 2017; 8(36): 60624-39.
[http://dx.doi.org/10.18632/oncotarget.17364] [PMID: 28947999]
[46]
Prestel M, Prell-Schicker C, Webb T, et al. The atherosclerosis risk variant rs2107595 mediates allele-specific transcriptional regulation of HDAC9 via E2F3 and Rb1. Stroke 2019; 50(10): 2651-60.
[http://dx.doi.org/10.1161/STROKEAHA.119.026112] [PMID: 31500558]
[47]
Rashid M, Zadeh LR, Baradaran B, et al. Up-down regulation of HIF-1α in cancer progression. Gene 2021; 798: 145796.
[http://dx.doi.org/10.1016/j.gene.2021.145796] [PMID: 34175393]

Rights & Permissions Print Cite
Article Metrics
31
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy