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Exp Clin Endocrinol Diabetes 2019; 127(04): 255-262
DOI: 10.1055/s-0043-125324
Article
© Georg Thieme Verlag KG Stuttgart · New York

Intravenous Injection of miR-34a Inhibitor Alleviates Diabetes Mellitus-Induced Vascular Endothelial Dysfunction by Targeting NOTCH1

Di Zhao
2   Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
,
Na-Sui Wang
1   Division of Endocrinology and Metabolism, Department of Medicine, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
,
Fu Chen
1   Division of Endocrinology and Metabolism, Department of Medicine, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
,
Zheng-Bing Li
1   Division of Endocrinology and Metabolism, Department of Medicine, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
,
Xi-Tao Li
1   Division of Endocrinology and Metabolism, Department of Medicine, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
,
Xu-Xin Zhu
1   Division of Endocrinology and Metabolism, Department of Medicine, the First Affiliated Hospital of Shantou University Medical College, Shantou, China
› Author Affiliations
Further Information

Publication History

received 30 November 2017
revised 30 November 2017

accepted 21 December 2017

Publication Date:
12 March 2018 (online)

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Abstract

Background miR-34a is a multifunctional post-translational modulator, which is involved in several diabetes-related complications. However, miR-34a remains to be fully elucidated in the diabetic endothelium from rats. In this study, the role of miR-34a/NOTCH1 signaling in the progression of hyperglycemia-vascular endothelial dysfunction was investigated.

Methods In intravenous injection of miR-34a mimics and inhibitors in streptozotocin (STZ)-induced diabetic rats, the biomarkers of endothelial dysfunction was measured. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The mRNA and protein levels were assayed by qRT-PCR and western blotting, respectively. Immunohistochemical staining was performed to measure NOTCH1 expression in the diabetic endothelium.

Results miR-34a was significantly up-regulated, and NOTCH1 down-regulated, in the thoracic aorta from STZ-induced diabetic rats compared with control group. As compared to model group, the mRNA of NOTCH1 was significantly decreased or increased by miR-34a mimics or inhibitors ex vivo, respectively. Bioinformatics methods further demonstrated that NOTCH1 was a potential target of miR-34a, which was confirmed by dual-luciferase reporter assay. Moreover, both serum ET and NO were significantly increased in diabetic rats as compared to control group. miR-34a inhibitors ex vivo treatment resulted in significant down-regulation ofserum ET and NO levels in diabetic rats as compared to model group.

Conclusion These results provide evidence to support the use of miR-34a inhibitors as a therapeutic approach attenuating hyperglycemia-induced vascular endothelial dysfunction.

Key words

diabetes - endothelial dysfunction - miR-34a - NOTCH1
 

  • References

  • 1 Diaz-de-Cerio E, Rodriguez-Nogales A, Algieri F. et al. The hypoglycemic effects of guava leaf (Psidium guajava L.) extract are associated with improving endothelial dysfunction in mice with diet-induced obesity. Food research international (Ottawa, Ont) 2017; 96: 64-71
    CrossrefPubMedGoogle Scholar
  • 2 Herder C, Dalmas E, Boni-Schnetzler M. et al. The IL-1 Pathway in Type 2 Diabetes and Cardiovascular Complications. Trends in endocrinology and metabolism: TEM 2015; 26: 551-563
    CrossrefPubMedGoogle Scholar
  • 3 Tabit CE, Shenouda SM, Holbrook M. et al. Protein kinase C-beta contributes to impaired endothelial insulin signaling in humans with diabetes mellitus. Circulation 2013; 127: 86-95
    CrossrefPubMedGoogle Scholar
  • 4 Ding H, Zhang T, Du Y. et al. HUCMNCs protect vascular endothelium and prevent ISR after endovascular interventional therapy for vascular diseases in T2DM rabbits. Molecular and cellular biochemistry 2017; DOI: 10.1007/s11010-017-3024-y.
    CrossrefPubMedGoogle Scholar
  • 5 Zhang Z, Jiang M, Xie X. et al. Oleanolic acid ameliorates high glucose-induced endothelial dysfunction via PPARdelta activation. Scientific reports 2017; 7: 40237
    CrossrefPubMedGoogle Scholar
  • 6 Kruger AL, Peterson S, Turkseven S. et al. D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes. Circulation 2005; 111: 3126-3134
    CrossrefPubMedGoogle Scholar
  • 7 Sukmawati D, Tanaka R, Ito-Hirano R. et al. The role of Notch signaling in diabetic endothelial progenitor cells dysfunction. Journal of diabetes and its complications 2016; 30: 12-20
    CrossrefPubMedGoogle Scholar
  • 8 Cao L, Arany PR, Wang YS. et al. Promoting angiogenesis via manipulation of VEGF responsiveness with notch signaling. Biomaterials 2009; 30: 4085-4093
    CrossrefPubMedGoogle Scholar
  • 9 Outtz HH, Tattersall IW, Kofler NM. et al. Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood 2011; 118: 3436-3439
    CrossrefPubMedGoogle Scholar
  • 10 Port JD, Sucharov C. Role of microRNAs in cardiovascular disease: therapeutic challenges and potentials. Journal of cardiovascular pharmacology 2010; 56: 444-453
    CrossrefPubMedGoogle Scholar
  • 11 Paranjape T, Heneghan H, Lindner R. et al. A 3'-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis. The Lancet Oncology 2011; 12: 377-386
    CrossrefPubMedGoogle Scholar
  • 12 Cruz LO, Hashemifar SS, Wu CJ. et al. Excessive expression of miR-27 impairs Treg-mediated immunological tolerance. The Journal of clinical investigation 2017; 127: 530-542
    CrossrefPubMedGoogle Scholar
  • 13 Ge L, Habiel DM, Hansbro PM. et al. miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways. 2016; 1: e90301
    PubMedGoogle Scholar
  • 14 Zhao B, Li H, Liu J. et al. MicroRNA-23b targets Ras GTPase-activating protein SH3 domain-binding Protein 2 to alleviate fibrosis and albuminuria in diabetic nephropathy. Journal of the American Society of Nephrology: JASN 2016; 27: 2597-2608
    CrossrefPubMedGoogle Scholar
  • 15 Zhang X, Song S, Luo H. Regulation of podocyte lesions in diabetic nephropathy via miR-34a in the Notch signaling pathway. Medicine 2016; 95: e5050
    PubMedGoogle Scholar
  • 16 Lin Y, Shen J, Li D. et al. MiR-34a contributes to diabetes-related cochlear hair cell apoptosis via SIRT1/HIF-1alpha signaling. General and comparative endocrinology 2017; 246: 63-70
    CrossrefPubMedGoogle Scholar
  • 17 Lu H, Hao L, Li S. et al. Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53-dependent pathway. Diabetologia 2016; 59: 1247-1257
    CrossrefPubMedGoogle Scholar
  • 18 Arunachalam G, Lakshmanan AP, Samuel SM. et al. Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin. The Journal of pharmacology and experimental therapeutics 2016; 356: 314-323
    CrossrefPubMedGoogle Scholar
  • 19 Li Q, Kim YR, Vikram A. et al. P66Shc-Induced MicroRNA-34a Causes Diabetic Endothelial Dysfunction by Downregulating Sirtuin1. Arteriosclerosis, thrombosis, and vascular biology 2016; 36: 2394-2403
    CrossrefPubMedGoogle Scholar
  • 20 Parlar A, Can C, Erol A. et al. Posttransplantation therapeutic rapamycin concentration protects nitric oxide-related vascular endothelial function: comparative effects in rat thoracic aorta and coronary endothelial cell culture. Transplantation proceedings 2010; 42: 1923-1930
    CrossrefPubMedGoogle Scholar
  • 21 Kimura I, Honda R, Okai H. et al. Vascular endothelial growth factor promotes cell-cycle transition from G0 to G1 phase in subcultured endothelial cells of diabetic rat thoracic aorta. Japanese journal of pharmacology 2000; 83: 47-55
    CrossrefPubMedGoogle Scholar
  • 22 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif) 2001; 25: 402-408
    CrossrefPubMedGoogle Scholar
  • 23 Zhang K, Wang D, Jiang Z. et al. Endothelial dysfunction correlates with decompression bubbles in rats. Scientific reports 2016; 6: 33390
    CrossrefPubMedGoogle Scholar
  • 24 Li Y, Zhang T, Zhou Y. et al. A Presenilin/Notch1 pathway regulated by miR-375, miR-30a, and miR-34a mediates glucotoxicity induced-pancreatic beta cell apoptosis. Scientific reports 2016; 6: 36136
    CrossrefPubMedGoogle Scholar
  • 25 Rawal S, Munasinghe PE, Shindikar A. et al. Down-regulation of proangiogenic microRNA-126 and microRNA-132 are early modulators of diabetic cardiac microangiopathy. Cardiovascular research 2017; 113: 90-101
    CrossrefPubMedGoogle Scholar
  • 26 Jiang P, Liu R, Zheng Y. et al. MiR-34a inhibits lipopolysaccharide-induced inflammatory response through targeting Notch1 in murine macrophages. Experimental cell research 2012; 318: 1175-1184
    CrossrefPubMedGoogle Scholar
  • 27 Fan C, Jia L, Zheng Y. et al. MiR-34a Promotes Osteogenic Differentiation of Human Adipose-Derived Stem Cells via the RBP2/NOTCH1/CYCLIN D1 Coregulatory Network. Stem cell reports 2016; 7: 236-248
    CrossrefPubMedGoogle Scholar
  • 28 Wei J, Shi Y, Zheng L. et al. miR-34 s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2. The Journal of cell biology 2012; 197: 509-521
    CrossrefPubMedGoogle Scholar
  • 29 Seyhan AA, Nunez Lopez YO, Xie H. et al. Pancreas-enriched miRNAs are altered in the circulation of subjects with diabetes: a pilot cross-sectional study. Scientific reports 2016; 6: 31479
    CrossrefPubMedGoogle Scholar
  • 30 Lavery CA, Kurowska-Stolarska M, Holmes WM. et al. miR-34a(-/-) mice are susceptible to diet-induced obesity. Obesity (Silver Spring, Md) 2016; 24: 1741-1751
    CrossrefPubMedGoogle Scholar
  • 31 Tugay K, Guay C, Marques AC. et al. Role of microRNAs in the age-associated decline of pancreatic beta cell function in rat islets. Diabetologia 2016; 59: 161-169
    CrossrefPubMedGoogle Scholar
  • 32 Liu ZJ, Xiao M, Balint K. et al. Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K/Akt pathways and requires MAML1. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2006; 20: 1009-1011
    CrossrefPubMedGoogle Scholar
  • 33 Yoon CH, Choi YE, Koh SJ. et al. High glucose-induced jagged 1 in endothelial cells disturbs notch signaling for angiogenesis: a novel mechanism of diabetic vasculopathy. Journal of molecular and cellular cardiology 2014; 69: 52-66
    CrossrefPubMedGoogle Scholar
  • 34 Pan S, Yang X, Jia Y. et al. Intravenous injection of microvesicle-delivery miR-130b alleviates high-fat diet-induced obesity in C57BL/6 mice through translational repression of PPAR-gamma. Journal of biomedical science 2015; 22: 86
    CrossrefPubMedGoogle Scholar
  • 35 Akao Y, Iio A, Itoh T. et al. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Molecular therapy: the journal of the American Society of Gene Therapy 2011; 19: 395-399
    CrossrefPubMedGoogle Scholar
  • 36 Zhang J, Shan WF, Jin TT. et al. Propofol exerts anti-hepatocellular carcinoma by microvesicle-mediated transfer of miR-142-3p from macrophage to cancer cells. Journal of translational medicine 2014; 12: 279
    CrossrefPubMedGoogle Scholar
  • 37 Liu Y, Zhao L, Li D. et al. Microvesicle-delivery miR-150 promotes tumorigenesis by up-regulating VEGF, and the neutralization of miR-150 attenuate tumor development. Protein & cell 2013; 4: 932-941
    CrossrefPubMedGoogle Scholar