Differential microRNA expression profiles and bioinformatics analysis between young and aging spontaneously hypertensive rats

Wang,Jingfeng; Zhang,Jingjing; Ding,Xuefeng; Wang,Yanyan; Li,Zhiming; Zhao,Weipeng; Jia,Jianguo; Zhou,Jingmin; Ge,Junbo

doi:10.3892/ijmm.2018.3370

Differential microRNA expression profiles and bioinformatics analysis between young and aging spontaneously hypertensive rats

Authors:
- Jingfeng Wang
- Jingjing Zhang
- Xuefeng Ding
- Yanyan Wang
- Zhiming Li
- Weipeng Zhao
- Jianguo Jia
- Jingmin Zhou
- Junbo Ge
View Affiliations

Affiliations: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China, Department of Cardiology, Zoucheng Hospital, Affiliated Hospital of Jining Medical University, Jining, Shandong 273500, P.R. China, Department of Cardiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637300, P.R. China, Department of Cardiology, People's Hospital of Nanbu County, Nanchong, Sichuan 637300, P.R. China
Published online on: January 9, 2018 https://doi.org/10.3892/ijmm.2018.3370
Pages: 1584-1594
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

MicroRNAs (miRNAs/miRs) serve a role as important regulators in cardiac hypertrophy. The present study aimed to reveal the differential expression profile of miRNAs between young and aging spontaneously hypertensive rats (SHRs) and studied the functional annotation of predicted targets. Briefly, 3‑month‑old and 12‑month‑old SHRs (n=3/group) were subjected to echocardiography, histopathological analysis and dihydroethidium staining. Subsequently, small RNA sequencing and data processing was conducted to identify the differentially expressed miRNAs between these two groups. Eight significantly upregulated miRNAs were validated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), followed by in silico target gene prediction. Functional annotation analysis of the predicted targets was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. As a result, significantly impaired left ventricular diastolic function was detected in the 12‑month‑old SHRs, alongside increased myocyte cross‑sectional area and percentage area of fibrosis, elevated reactive oxygen species production and reduced microvessel density (P<0.05). Compared with the 3‑month‑old SHRs, 21 miRNAs were significantly upregulated and five miRNAs were downregulated in 12‑month‑old rats (P<0.05). Eight upregulated, remodeling‑associated miRNAs, including rno‑miR‑132‑3p, rno‑miR‑182, rno‑miR‑208b‑3p, rno‑miR‑212‑3p, rno‑miR‑214‑3p, rno‑miR‑218a‑5p, rno‑miR‑221‑3p and rno‑miR‑222‑3p, underwent bioinformatics analysis. The target genes were significantly enriched in 688 GO terms and 39 KEGG pathways, including regulation of peptidyl‑tyrosine phosphorylation, regulation of protein serine/threonine kinase activity, adrenergic signaling in cardiomyocytes, ErbB signaling pathway, mTOR signaling pathway, FoxO signaling pathway, Ras signaling pathway, insulin secretion, adipocytokine signaling pathway, HIF‑1 signaling pathway, Rap1 signaling pathway, VEGF signaling pathway and TNF signaling pathway. Collectively, the present study identified a dysregulated miRNA profile in aging SHRs, which targeted numerous signaling pathways associated with cardiac hypertrophy, autophagy, insulin metabolism, angiogenesis and inflammatory response.

View Figures

View References

1	Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL and Redfield MM: Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 355:251–259. 2006. View Article : Google Scholar : PubMed/NCBI
2	Cingolani OH, Yang XP, Cavasin MA and Carretero OA: Increased systolic performance with diastolic dysfunction in adult spontaneously hypertensive rats. Hypertension. 41:249–254. 2003. View Article : Google Scholar : PubMed/NCBI
3	Messerli FH, Rimoldi SF and Bangalore S: The transition from hypertension to heart failure: Contemporary update. JACC Heart Fail. 5:543–551. 2017. View Article : Google Scholar : PubMed/NCBI
4	Gu H, Li Y, Fok H, Simpson J, Kentish JC, Shah AM and Chowienczyk PJ: Reduced first-phase ejection fraction and sustained myocardial wall stress in hyptensive patients with diastolic dysfunction: A manifestation of impaired shortening deactivation that links systolic to diastolic dysfunction and preserves systolic ejection fraction. Hypertesion. 69:633–640. 2017. View Article : Google Scholar
5	Slama M, Ahn J, Varagic J, Susic D and Frohlich ED: Long-term left ventricular echocardiographic follow-up of SHR and WKY rats: Effects of hypertension and age. Am J Physiol Heart Circ Physiol. 286:H181–H185. 2004. View Article : Google Scholar
6	Rysä J, Leskinen H, Ilves M and Ruskoaho H: Distinct upregulation of extracellular matrix genes in transition from hypertrophy to hypertensive heart failure. Hypertension. 45:927–933. 2005. View Article : Google Scholar : PubMed/NCBI
7	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta c(T)). Method Methods. 25:402–408. 2001. View Article : Google Scholar
8	Ucar A, Gupta SK, Fiedler J, Erikci E, Kardasinski M, Batkai S, Dangwal S, Kumarswamy R, Bang C, Holzmann A, et al: The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat Commun. 3:10782012. View Article : Google Scholar : PubMed/NCBI
9	Yang T, Gu H, Chen X, Fu S, Wang C, Xu H, Feng Q and Ni Y: Cardiac hypertrophy and dysfunction induced by overexpression of miR-21. in vivo J Surg Res. 192:317–325. 2014. View Article : Google Scholar
10	Su M, Wang J, Wang C, Wang X, Dong W, Qiu W, Wang Y, Zhao X, Zou Y, Song L, et al: MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis. Cell Death Differ. 22:986–999. 2015. View Article : Google Scholar :
11	Wang C, Wang S, Zhao P, Wang X, Wang J, Wang Y, Song L, Zou Y and Hui R: MiR-221 promotes cardiac hypertrophy in vitro through the modulation of p27 expression. J Cell Biochem. 113:2040–2046. 2012. View Article : Google Scholar : PubMed/NCBI
12	Oliveira-Carvalho V, Carvalho VO and Bocchi EA: The emerging role of miR-208a in the heart. DNA Cell Biol. 32:8–12. 2013. View Article : Google Scholar
13	Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K and Tobe K: Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 116:1784–1792. 2006. View Article : Google Scholar : PubMed/NCBI
14	Hong SJ, Park CG, Seo HS, Oh DJ and Ro YM: Associations among plasma adiponectin, hypertension, left ventricular diastolic function and left ventricular mass index. Blood Press. 13:236–242. 2004. View Article : Google Scholar : PubMed/NCBI
15	Chen CF, Huang J, Li H, Zhang C, Huang X, Tong G and Xu YZ: MicroRNA-221 regulates endothelial nitric oxide production and inflammatory response by targeting adiponectin receptor 1. Gene. 565:246–251. 2015. View Article : Google Scholar : PubMed/NCBI
16	Du H, Fu Z, He G, Wang Y, Xia G, Fang M and Zhang T: MicroRNA-218 targets adiponectin receptor 2 to regulate adiponectin signaling. Mol Med Rep. 11:4701–4705. 2015. View Article : Google Scholar : PubMed/NCBI
17	Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, Pfeffer S, Tuschl T, Rajewsky N, Rorsman P and Stoffel M: A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 432:226–230. 2004. View Article : Google Scholar : PubMed/NCBI
18	Li N, Hwangbo C, Jaba IM, Zhang J, Papangeli I, Han J, Mikush N, Larrivée B, Eichmann A, Chun HJ, et al: miR-182 modulates myocardial Hypertrophic response induced by angiogenesis in heart. Sci Rep. 6:212282016. View Article : Google Scholar : PubMed/NCBI
19	Shimizu I and Minamino T: Physiological and pathological cardiac hypertrophy. J Mol cell cardiol. 97:245–262. 2016. View Article : Google Scholar : PubMed/NCBI
20	Duan Q, Yang L, Gong W, Chaugai S, Wang F, Chen C, Wang P, Zou MH and Wang DW: MicroRNA-214 is upregulated in heart failure patients and suppresses XBP1-mediated endothelial cells angiogenesis. J Cell Physiol. 230:1964–1973. 2015. View Article : Google Scholar : PubMed/NCBI
21	Chistiakov DA, Sobenin IA, Orekhov AN and Bobryshev YV: Human miR-221/222 in physiological and atherosclerotic vascular remodeling. BioMed Res Int. 2015:3545172015. View Article : Google Scholar : PubMed/NCBI
22	Goren Y, Kushnir M, Zafrir B, Tabak S, Lewis BS and Amir O: Serum levels of microRNAs in patients with heart failure. Eur J Heart Fail. 14:147–154. 2012. View Article : Google Scholar
23	Bertagnolli M, Schenkel PC, Campos C, Mostarda CT, Casarini DE, Belló-Klein A, Irigoyen MC and Rigatto K: Exercise training reduces sympathetic modulation on cardiovascular system and cardiac oxidative stress in spontaneously hypertensive rats. Am J Hypertens. 21:1188–1193. 2008. View Article : Google Scholar : PubMed/NCBI
24	Barki-Harrington L, Perrino C and Rockman HA: Network integration of the adrenergic system in cardiac hypertrophy. Cardiovasc Res. 63:391–402. 2004. View Article : Google Scholar : PubMed/NCBI
25	Sysa-Shah P, Xu Y, Guo X, Belmonte F, Kang B, Bedja D, Pin S, Tsuchiya N and Gabrielson K: Cardiac-specific over-expression of epidermal growth factor receptor 2 (ErbB2) induces pro-survival pathways and hypertrophic cardiomyopathy in mice. PLoS One. 7:e428052012. View Article : Google Scholar : PubMed/NCBI
26	Rohrbach S, Yan X, Weinberg EO, Hasan F, Bartunek J, Marchionni MA and Lorell BH: Neuregulin in cardiac hypertrophy in rats with aortic stenosis. Differential expression of erbB2 and erbB4 receptors. Circulation. 100:407–412. 1999. View Article : Google Scholar : PubMed/NCBI
27	Hua Y, Zhang Y, Ceylan-Isik AF, Wold LE, Nunn JM and Ren J: Chronic Akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: Role of autophagy. Basic Res Cardiol. 106:1173–1191. 2011. View Article : Google Scholar : PubMed/NCBI
28	Ni YG, Berenji K, Wang N, Oh M, Sachan N, Dey A, Cheng J, Lu G, Morris DJ, Castrillon DH, et al: Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Circulation. 114:1159–1168. 2006. View Article : Google Scholar : PubMed/NCBI
29	Sengupta A, Molkentin JD and Yutzey KE: FoxO transcription factors promote autophagy in cardiomyocytes. J Biol Chem. 284:28319–28331. 2009. View Article : Google Scholar : PubMed/NCBI
30	Gelb BD and Tartaglia M: RAS signaling pathway mutations and hypertrophic cardiomyopathy: Getting into and out of the thick of it. J Clin Invest. 121:844–847. 2011. View Article : Google Scholar : PubMed/NCBI
31	Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K, et al: Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med. 10:1384–1389. 2004. View Article : Google Scholar : PubMed/NCBI
32	Carmona G, Göttig S, Orlandi A, Scheele J, Bäuerle T, Jugold M, Kiessling F, Henschler R, Zeiher AM, Dimmeler S and Chavakis E: Role of the small GTPase Rap1 for integrin activity regulation in endothelial cells and angiogenesis. Blood. 113:488–497. 2009. View Article : Google Scholar
33	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
34	Zhang H, Yang H, Zhang C, Jing Y, Wang C, Liu C, Zhang R, Wang J, Zhang J, Zen K, et al: Investigation of microRNA expression in human serum during the aging process. J Gerontol A Biol Sci Med Sci. 70:102–109. 2015. View Article : Google Scholar
35	Rippe C, Blimline M, Magerko KA, Lawson BR, LaRocca TJ, Donato AJ and Seals DR: MicroRNA changes in human arterial endothelial cells with senescence: Relation to apoptosis, eNOS and inflammation. Exp Gerontol. 47:45–51. 2012. View Article : Google Scholar