miR‑126a‑5p‑Dbp and miR‑31a‑Crot/Mrpl4 interaction pairs crucial for the development of hypertension and stroke

Zhao,Qini; Sun,Huan; Yin,Liquan; Wang,Libo

doi:10.3892/mmr.2019.10679

miR‑126a‑5p‑Dbp and miR‑31a‑Crot/Mrpl4 interaction pairs crucial for the development of hypertension and stroke

Authors:
- Qini Zhao
- Huan Sun
- Liquan Yin
- Libo Wang
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Affiliations: Department of Cardiology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China, Department of Rehabilitation Medicine, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China, Department of Neurology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
Published online on: September 12, 2019 https://doi.org/10.3892/mmr.2019.10679
Pages: 4151-4167
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to integrate the mRNA and microRNA (miRNA) expression profiles of spontaneously hypertensive rats (SHR rats) and stroke‑prone spontaneously hypertensive rats (SHRSP rats) to screen for potential therapeutic targets for hypertension and stroke. The datasets GSE41452, GSE31457, GSE41453 and GSE53363 were collected from the Gene Expression Omnibus (GEO) database to screen differentially expressed genes (DEGs). The GSE53361 dataset was obtained to analyze differentially expressed miRNAs (DEMs). The DEGs and DEMs were identified between SHR (or SHRSP) rats and normotensive Wistar‑Kyoto (WKY) rats using the Linear Models for Microarray (limma) data method. Venn diagrams were used to show the SHR‑specific, SHRSP‑specific and SHR‑SHRSP shared DEGs and DEMs, and these were utilized to construct the protein‑protein interaction (PPI) and miRNA‑mRNA regulatory networks. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to explore the function of the genes. Subsequently, the connectivity Map (CMAP) database was searched to identify small‑molecule drugs. Comparisons between the GSE41452‑GSE31457‑GSE41453 merged and GSE53363 datasets identified 2 SHR‑specific, 8 SHRSP‑specific and 15 SHR‑SHRSP shared DEGs. Function enrichment analysis showed that SHRSP‑specific D‑box binding PAR bZIP transcription factor (Dbp) was associated with circadian rhythm, and SHR‑SHRSP shared carnitine O‑octanoyltransferase (Crot) was involved in fatty acid metabolic processes or the inflammatory response via interacting with epoxide hydrolase 2 (EPHX2). SHR‑SHRSP shared mitochondrial ribosomal protein L4 (Mrpl4) may exert roles by interacting with the threonine‑tRNA ligase, TARS2. The miRNA regulatory network predicted that upregulated Dbp could be regulated by rno‑miR‑126a‑5p, whereas downregulated Crot and Mrpl4 could be modulated by rno‑miR‑31a. The CMAP database predicted that small‑molecule drugs, including botulin, Gly‑His‑Lys, and podophyllotoxin, may possess therapeutic potential. In conclusion, the present study has identified Dbp, Crot and Mrpl4 as potential targets for the treatment of hypertension and stroke. Furthermore, the expression of these genes may be reversed by the above miRNAs or drugs.

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1	Kim IG, So WY and Sung DJ: The relationships between lifestyle factors and hypertension in community-dwelling Korean adults. J Phys Ther Sci. 27:3689–3692. 2015. View Article : Google Scholar : PubMed/NCBI
2	Kupferman JC, Zafeiriou DI, Lande MB, Kirkham FJ and Pavlakis SG: Stroke and hypertension in children and adolescents. J Child Neurol. 32:408–417. 2017. View Article : Google Scholar : PubMed/NCBI
3	Alloubani A, Saleh A and Abdelhafiz I: Hypertension and diabetes mellitus as a predictive risk factors for stroke. Diabetes Metab Syndr. 12:577–584. 2018. View Article : Google Scholar : PubMed/NCBI
4	Shambesh MKA, Emahbes TM, Saleh ZE, Elosta MAA and Shambesh IM: Role of hypertension as a major risk factor of stroke in Africa; Libya: Community based survey. British J Medicine Med Res. 9:1–11. 2015. View Article : Google Scholar
5	Adil MM, Beslow LA, Qureshi AI, Malik AA and Jordan LC: Hypertension is associated with increased mortality in children hospitalized with arterial ischemic stroke. Pediatr Neurol. 56:25–29. 2016. View Article : Google Scholar : PubMed/NCBI
6	Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, Wang L, Jiang Y, Li Y, Wang Y, et al: Prevalence, incidence, and mortality of stroke in China: Results from a nationwide population-based survey of 480 687 adults. Circulation. 135:759–771. 2017. View Article : Google Scholar : PubMed/NCBI
7	McGrath R, Markides K, Hall O and Peterson M: The burden of health conditions for middle-aged and older adults in the United States: Disability-adjusted life years. BMC Geriatr. 19:1002019. View Article : Google Scholar : PubMed/NCBI
8	Rubattu S, Cotugno M, Bianchi F, Sironi L, Gelosa P, Stanzione R, Forte M, De Sanctis C, Madonna M, Marchitti S, et al: A differential expression of uncoupling protein-2 associates with renal damage in stroke-resistant spontaneously hypertensive rat/stroke-prone spontaneously hypertensive rat-derived stroke congenic lines. J Hypertens. 35:1857–1871. 2017. View Article : Google Scholar : PubMed/NCBI
9	Lan C, Chen X, Zhang Y, Wang W, Wang WE, Liu Y, Cai Y, Ren H, Zheng S, Zhou L and Zeng C: Curcumin prevents strokes in stroke-prone spontaneously hypertensive rats by improving vascular endothelial function. BMC Cardiovasc Disord. 18:432018. View Article : Google Scholar : PubMed/NCBI
10	Yoshida M, Watanabe Y, Yamanishi K, Yamashita A, Yamamoto H, Okuzaki D, Shimada K, Nojima H, Yasunaga T, Okamura H, et al: Analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: gene expression profiles in the brain. Int J Mol Med. 33:887–896. 2014. View Article : Google Scholar : PubMed/NCBI
11	Yamamoto H, Okuzaki D, Yamanishi K, Xu Y, Watanabe Y, Yoshida M, Yamashita A, Goto N, Nishiguchi S, Shimada K, et al: Genetic analysis of genes causing hypertension and stroke in spontaneously hypertensive rats. Int J Mol Med. 31:1057–1065. 2013. View Article : Google Scholar : PubMed/NCBI
12	Watanabe Y, Yoshida M, Yamanishi K, Yamamoto H, Okuzaki D, Nojima H, Yasunaga T, Okamura H, Matsunaga H and Yamanishi H: Genetic analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: Gene expression profiles in the kidneys. Int J Mol Med. 36:712–724. 2015. View Article : Google Scholar : PubMed/NCBI
13	Palao T, Swärd K, Jongejan A, Moerland PD, de Vos J, van Weert A, Arribas SM, Groma G, vanBavel E and Bakker EN: Gene expression and MicroRNA expression analysis in small arteries of spontaneously hypertensive rats. Evidence for ER stress. PLoS One. 10:e01370272015. View Article : Google Scholar : PubMed/NCBI
14	Nemoto K, Ikeda A, Ito S, Miyata M, Yoshida C and Degawa M: Comparison of constitutive gene expression levels of hepatic cholesterol biosynthetic enzymes between Wistar-Kyoto and stroke-prone spontaneously hypertensive rats. Biol Pharm Bull. 36:1216–1220. 2013. View Article : Google Scholar : PubMed/NCBI
15	Rubattu S, Stanzione R, Bianchi F, Cotugno M, Forte M, Ragione FD, Fioriniello S, D'Esposito M, Marchitti S, Madonna M, et al: Reduced brain UCP2 expression mediated by microRNA-503 contributes to increased stroke susceptibility in the high-salt fed stroke-prone spontaneously hypertensive rat. Cell Death Dis. 8:e28912017. View Article : Google Scholar : PubMed/NCBI
16	Matsuoka H, Tamura A, Kinehara M, Shima A, Uda A, Tahara H and Michihara A: Levels of tight junction protein CLDND1 are regulated by microRNA-124 in the cerebellum of stroke-prone spontaneously hypertensive rats. Biochem Biophys Res Commun. 498:817–823. 2018. View Article : Google Scholar : PubMed/NCBI
17	Diboun I, Wernisch L, Orengo CA and Koltzenburg M: Microarray analysis after RNA amplification can detect pronounced differences in gene expression using limma. BMC Genomics. 7:2522006. View Article : Google Scholar : PubMed/NCBI
18	Green GH and Diggle PJ: On the operational characteristics of the benjamini and hochberg false discovery rate procedure. Stat Appl Genet Mol Biol. 6:272007. View Article : Google Scholar
19	Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al: STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43:D447–D452. 2015. View Article : Google Scholar : PubMed/NCBI
20	Kohl M, Wiese S and Warscheid B: Cytoscape: Software for visualization and analysis of biological networks. Methods Mol Biol. 696:291–303. 2011. View Article : Google Scholar : PubMed/NCBI
21	Dweep H and Gretz N: miRWalk2. 0: A comprehensive atlas of microRNA-target interactions. Nat Methods. 12:6972015. View Article : Google Scholar : PubMed/NCBI
22	Huang DW, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
23	Subramanian A, Narayan R, Corsello SM, Peck DD, Natoli TE, Lu X, Gould J, Davis JF, Tubelli AA, Asiedu JK, et al: A next generation connectivity map: L1000 platform and the first 1,000,000 Profiles. Cell. 171:1437–1452.e17. 2017. View Article : Google Scholar : PubMed/NCBI
24	Zhixiang Y, Cheng W, Jibing X, Bisheng G, Ming X and Deyu L: Ambulatory blood pressure monitoring in children suffering from orthostatic hypertension. Biomed Eng Online. 17:1292018. View Article : Google Scholar : PubMed/NCBI
25	Kario K, Pickering TG, Matsuo T, Hoshide S, Schwartz JE and Shimada K: Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension. 38:852–857. 2001. View Article : Google Scholar : PubMed/NCBI
26	Mateo-Gavira I, Vílchez-López FJ, García-Palacios MV, Laureano CS, Jiménez-Carmona S and Aguilar-Diosdado M: Nocturnal blood pressure is associated with the progression of microvascular complications and hypertension in patients with type 1 diabetes mellitus. J Diabetes Complications. 30:1326–1332. 2016. View Article : Google Scholar : PubMed/NCBI
27	Castilla-Guerra L, Espino-Montoro A, Fernández-Moreno MC and López-Chozas JM: Abnormal blood pressure circadian rhythm in acute ischaemic stroke: Are lacunar strokes really different? Int J Stroke. 4:257–261. 2010. View Article : Google Scholar
28	Yan B, Peng L, Dong Q, Zheng F, Yang P, Sun L, Gong S, Zeng L and Wang G: Reverse-dipper pattern of blood pressure may predict lacunar infarction in patients with essential hypertension. Eur J Neurol. 22:1022–1025. 2015. View Article : Google Scholar : PubMed/NCBI
29	Richards J, Diaz AN and Gumz ML: Clock genes in hypertension: novel insights from rodent models. Blood Press Monit. 19:249–254. 2014. View Article : Google Scholar : PubMed/NCBI
30	Leu HB, Chung CM, Lin SJ, Chiang KM, Yang HC, Ho HY, Ting CT, Lin TH, Sheu SH, Tsai WC, et al: Association of circadian genes with diurnal blood pressure changes and non-dipper essential hypertension: A genetic association with young-onset hypertension. Hypertens Res. 38:155–162. 2015. View Article : Google Scholar : PubMed/NCBI
31	Corella D, Asensio EM, Coltell O, Sorlí JV, Estruch R, Martínez-González MÁ, Salas-Salvadó J, Castañer O, Arós F, Lapetra J, et al: CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: Dietary modulation in the PREDIMED randomized trial. Cardiovasc Diabetol. 15:42016. View Article : Google Scholar : PubMed/NCBI
32	Kurbatova IV, Topchieva LV, Korneva VA, Kolomeichuk SN and Nemova NN: Expression of circadian rhythm genes CLOCK, BMAL1, and PER1 in buccal epithelial cells of patients with essential arterial hypertension in dependence on polymorphic variants of CLOCK and BMAL1 genes. Bull Exp Biol Med. 157:360–363. 2014. View Article : Google Scholar : PubMed/NCBI
33	Douma LG, Solocinski K, Holzworth MR, Crislip GR, Masten SH, Miller AH, Cheng KY, Lynch IJ, Cain BD, Wingo CS and Gumz ML: Female C57BL/6J mice lacking the circadian clock protein PER1 are protected from nondipping hypertension. Am J Physiol Regul Integr Comp Physiol. 316:R50–R58. 2019. View Article : Google Scholar : PubMed/NCBI
34	Alli AA, Yu L, Holzworth M, Richards J, Cheng KY, Lynch IJ, Wingo CS and Gumz ML: Direct and indirect inhibition of the circadian clock protein PER1: Effects on ENaC and blood pressure. Am J Physiol Renal Physiol. 316:F807–F813. 2019. View Article : Google Scholar : PubMed/NCBI
35	Lembach A, Stahr A, Ali AAH, Ingenwerth M and von Gall C: Sex-dependent effects of bmal1-deficiency on mouse cerebral cortex infarction in response to photothrombotic stroke. Int J Mol Sci. 19(pii): E31242018. View Article : Google Scholar : PubMed/NCBI
36	Yoshiro N, Takeshi T, Daizo K, Takahiro O, Shinji M, Miho M, Tsuyoshi S, Yoshio F, Mitsumasa O and Tadaaki I: Circadian gene expression of clock genes and plasminogen activator inhibitor-1 in heart and aorta of spontaneously hypertensive and Wistar-Kyoto rats. J Hypertens. 21:1107–1115. 2003. View Article : Google Scholar : PubMed/NCBI
37	Jin F and Xing J: Circulating miR-126 and miR-130a levels correlate with lower disease risk, disease severity, and reduced inflammatory cytokine levels in acute ischemic stroke patients. Neurol Sci. 39:1757–1765. 2018. View Article : Google Scholar : PubMed/NCBI
38	Jin F and Xing J: Circulating pro-angiogenic and anti-angiogenic microRNA expressions in patients with acute ischemic stroke and their association with disease severity. Neurol Sci. 38:2015–2023. 2017. View Article : Google Scholar : PubMed/NCBI
39	Geng W, Tang H, Luo S, Lv Y, Liang D, Kang X and Hong W: Exosomes from miRNA-126-modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation. Am J Transl Res. 11:780–792. 2019.PubMed/NCBI
40	Pan Q, Zheng J, Du D, Liao X, Ma C, Yang Y, Chen Y, Zhong W and Ma X: MicroRNA-126 priming enhances functions of endothelial progenitor cells under physiological and hypoxic conditions and their therapeutic efficacy in cerebral ischemic damage. Stem Cells Int. 2018:29123472018. View Article : Google Scholar : PubMed/NCBI
41	Vega-Badillo J, Gutiérrez-Vidal R, Hernández-Pérez HA, Villamil-Ramírez H, León-Mimila P, Sánchez-Muñoz F, Morán-Ramos S, Larrieta-Carrasco E, Fernández-Silva I, Méndez-Sánchez N, et al: Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects. Liver Int. 36:1383–1391. 2016. View Article : Google Scholar : PubMed/NCBI
42	Rottiers V and Näär AM: MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol. 13:239–250. 2012. View Article : Google Scholar : PubMed/NCBI
43	Kim S, Sohn I and Lee YS and Lee YS: Hepatic gene expression profiles are altered by genistein supplementation in mice with diet-induced obesity. J Nutr. 135:33–41. 2005. View Article : Google Scholar : PubMed/NCBI
44	Roush GC: Obesity-induced hypertension: Heavy on the accelerator. J Am Heart Assoc. 8:e0123342019. View Article : Google Scholar : PubMed/NCBI
45	Mitchell AB, Cole JW, McArdle PF, Cheng YC, Ryan KA, Sparks MJ, Mitchell BD and Kittner SJ: Obesity increases risk of ischemic stroke in young adults. Stroke. 46:1690–1692. 2015. View Article : Google Scholar : PubMed/NCBI
46	Irwin DC, Garat CV, Crossno JT Jr, Maclean PS, Sullivan TM, Erickson PF, Jackman MR, Harral JW, Reusch JEB and Klemm DJ: Obesity-related pulmonary arterial hypertension in rats correlates with increased circulating inflammatory cytokines and lipids and with oxidant damage in the arterial wall but not with hypoxia. Pulm Circ. 4:638–653. 2014. View Article : Google Scholar : PubMed/NCBI
47	Maysami S, Haley MJ, Gorenkova N, Krishnan S, McColl BW and Lawrence CB: Prolonged diet-induced obesity in mice modifies the inflammatory response and leads to worse outcome after stroke. J Neuroinflammation. 12:1402015. View Article : Google Scholar : PubMed/NCBI
48	Ulu A, Harris TR, Morisseau C, Miyabe C, Inoue H, Schuster G, Dong H, Iosif AM, Liu JY, Weiss RH, et al: Anti-inflammatory effects of ω-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension. J Cardiovasc Pharmacol. 62:285–297. 2013. View Article : Google Scholar : PubMed/NCBI
49	Xu N, Meisgen F, Butler LM, Han G, Wang XJ, Söderberg-Nauclér C, Ståhle M, Pivarcsi A and Sonkoly E: MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40. J Immunol. 190:678–688. 2013. View Article : Google Scholar : PubMed/NCBI
50	Benita Y, Kikuchi H, Smith AD, Zhang MQ, Chung DC and Xavier RJ: An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia. Nucleic Acids Res. 37:4587–4602. 2009. View Article : Google Scholar : PubMed/NCBI
51	Ritz MF, Fluri F, Engelter ST, Schaeren-Wiemers N and Lyrer PA: Cortical and putamen age-related changes in the microvessel density and astrocyte deficiency in spontaneously hypertensive and stroke-prone spontaneously hypertensive rats. Curr Neurovasc Res. 6:279–287. 2009. View Article : Google Scholar : PubMed/NCBI
52	Liu D, Lei L, Desir M, Huang Y, Cleman J, Jiang W, Fernandez-Hernando C, Di Lorenzo A, Sessa WC and Giordano FJ: Smooth muscle hypoxia-inducible factor 1α links intravascular pressure and atherosclerosis-brief report. Arterioscler Thromb Vasc Biol. 36:442–445. 2016. View Article : Google Scholar : PubMed/NCBI
53	Barteczek P, Li L, Ernst AS, Böhler LI, Marti HH and Kunze R: Neuronal HIF-1α and HIF-2α deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke. J Cereb Blood Flow Metab. 37:291–306. 2017. View Article : Google Scholar : PubMed/NCBI
54	Williams TF, Mirando AC, Wilkinson B, Francklyn CS and Lounsbury KM: Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis. Sci Rep. 3:13172013. View Article : Google Scholar : PubMed/NCBI
55	Zhai ZY and Feng J: Constraint-induced movement therapy enhances angiogenesis and neurogenesis after cerebral ischemia/reperfusion. Neural Regen Res. 14:1743–1754. 2019. View Article : Google Scholar : PubMed/NCBI
56	Lora VR, Clemente-Napimoga JT, Abdalla HB, Macedo CG, Canales GT and Barbosa CM: Botulinum toxin type A reduces inflammatory hypernociception induced by arthritis in the temporomadibular joint of rats. Toxicon. 129:52–57. 2017. View Article : Google Scholar : PubMed/NCBI
57	Wang L, Wang K, Chu X, Li T, Shen N, Fan C, Niu Z, Zhang X and Hu L: Intra-articular injection of Botulinum toxin A reduces neurogenic inflammation in CFA-induced arthritic rat model. Toxicon. 126:70–78. 2017. View Article : Google Scholar : PubMed/NCBI
58	Gruchlik A, Jurzak M, Chodurek E and Dzierzewicz Z: Effect of Gly-Gly-His, Gly-His-Lys and their copper complexes on TNF-alpha-dependent IL-6 secretion in normal human dermal fibroblasts. Acta Pol Pharm. 69:1303–1306. 2012.PubMed/NCBI
59	Kalita B, Ranjan R, Singh A, Yashavarddhan MH, Bajaj S and Gupta ML: A combination of podophyllotoxin and rutin attenuates radiation induced gastrointestinal injury by negatively regulating NF-κB/p53 signaling in lethally irradiated mice. PLoS One. 11:e01685252010. View Article : Google Scholar