An RNA‑sequencing study identifies candidate genes for angiotensin II‑induced cardiac remodeling

Shu,Jin; Liu,Zhanwen; Jin,Li; Wang,Haiya

doi:10.3892/mmr.2017.8043

An RNA‑sequencing study identifies candidate genes for angiotensin II‑induced cardiac remodeling

Authors:
- Jin Shu
- Zhanwen Liu
- Li Jin
- Haiya Wang
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Affiliations: Department of Gerontology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China, Department of Pharmacy, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China, Department of Gerontology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200001, P.R. China
Published online on: November 14, 2017 https://doi.org/10.3892/mmr.2017.8043
Pages: 1954-1962

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Abstract

The present study aimed to reveal the underlying mechanism of angiotensin II (AngII)‑induced cardiac remodeling and to identify potential therapeutic targets for prevention. Rat cardiac fibroblasts (CFs) were cultured with 10 nM AngII for 12 h, and CFs without AngII were used as the control. Following RNA isolation from AngII treated and control CFs, RNA‑sequencing was performed to detect gene expression levels. Differentially‑expressed genes (DEGs) were identified using the linear models for microarray analysis package in R software, and their functions and pathways were examined via enrichment analysis. In addition, potential associations at the protein level were revealed via the construction of a protein‑protein interaction (PPI) network. The expression levels of genes of interest were validated via reverse transcription‑quantitative polymerase chain reaction analysis. In total, 126 upregulated and 140 downregulated DEGs were identified. According to the enrichment analysis, acetyl coA carboxylase β (ACACB), interleukin 1β (IL1B), interleukin 1α (IL1A), nitric oxide synthase 2 (NOS2) and matrix metallopeptidase 3 (MMP3) were associated with the immune response, regulation of angiogenesis, superoxide metabolic process and carboxylic acid binding biological processes. Among them, ACACB and MPP3 were two predominant nodes in the PPI network. In addition, IL1B and MMP3 were demonstrated to be upregulated. These five genes, particularly IL1B and MMP3, may be used as candidate markers for the prevention of AngII‑induced cardiac remodeling.

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1	Takano H, Hasegawa H, Nagai T and Komuro I: Implication of cardiac remodeling in heart failure: Mechanisms and therapeutic strategies. Intern Med. 42:465–469. 2003. View Article : Google Scholar
2	Bujak M and Frangogiannis NG: The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 74:184–195. 2007. View Article : Google Scholar
3	Iwanaga K, Takano H, Ohtsuka M, Hasegawa H, Zou Y, Qin Y, Odaka K, Hiroshima K, Tadokoro H and Komuro I: Effects of G-CSF on cardiac remodeling after acute myocardial infarction in swine. Biochem Biophys Res Commun. 325:1353–1359. 2004. View Article : Google Scholar
4	Grobe JL, Mecca AP, Lingis M, Shenoy V, Bolton TA, Machado JM, Speth RC, Raizada MK and Katovich MJ: Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1–7). Am J Physiol Heart Circ Physiol. 292:H736–H742. 2007. View Article : Google Scholar
5	Huang XR, Chung AC, Yang F, Yue W, Deng C, Lau CP, Tse HF and Lan HY: Smad3 mediates cardiac inflammation and fibrosis in angiotensin II-induced hypertensive cardiac remodeling. Hypertension. 55:1165–1171. 2010. View Article : Google Scholar
6	Hu C, Dandapat A, Sun L, Marwali MR, Inoue N, Sugawara F, Inoue K, Kawase Y, Jishage K, Suzuki H, et al: Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion. Hypertension. 52:556–562. 2008. View Article : Google Scholar
7	McCalmon SA, Desjardins DM, Ahmad S, Davidoff KS, Snyder CM, Sato K, Ohashi K, Kielbasa OM, Mathew M, Ewen EP, et al: Modulation of angiotensin II-mediated cardiac remodeling by the MEF2A target gene Xirp2. Circ Res. 106:952–960. 2010. View Article : Google Scholar :
8	Yang D, Yuan J, Liu G, Ling Z, Zeng H, Chen Y, Zhang Y, She Q and Zhou X: Angiotensin receptor blockers and statins could alleviate atrial fibrosis via regulating platelet-derived growth factor/Rac1/nuclear factor-kappa B Axis. Int J Med Sci. 10:812–824. 2013. View Article : Google Scholar :
9	Chomczynski P and Sacchi N: The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: Twenty-something years on. Nat Protoc. 1:581–585. 2006. View Article : Google Scholar
10	Ran M, Chen B and Li Z, Wu M, Liu X, He C, Zhang S and Li Z: Systematic identification of long noncoding RNAs in immature and mature porcine testes. Biol Reprod. 94:772016. View Article : Google Scholar
11	Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT and Salzberg SL: StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 33:290–295. 2015. View Article : Google Scholar :
12	Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, Guo Y, Stephens R, Baseler MW, Lane HC and Lempicki RA: DAVID bioinformatics resources: Expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 35:(Web Server Issue). W169–W175. 2007. View Article : Google Scholar :
13	Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, Doerks T, Stark M, Muller J, Bork P, et al: The STRING database in 2011: Functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 39:(Database Issue). D561–D568. 2011. View Article : Google Scholar
14	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
15	Santulli G: Sympathetic nervous system signaling in heart failure and cardiac aging. Pathophysiol Pharm Cardio Disease. 83–105. 2015.
16	Perrino C and Rockman HA: Reversal of cardiac remodeling by modulation of adrenergic receptors: A new frontier in heart failure. Curr Opin Cardiol. 22:443–449. 2007. View Article : Google Scholar
17	Karnik SS and Unal H: Angiotensin II receptor-induced cardiac remodeling in mice without angiotensin II. Hypertension. 59:542–544. 2012. View Article : Google Scholar :
18	Ables GP, Ouattara A, Hampton TG, Cooke D, Perodin F, Augie I and Orentreich DS: Dietary methionine restriction in mice elicits an adaptive cardiovascular response to hyperhomocysteinemia. Sci Rep. 5:88862015. View Article : Google Scholar :
19	Hwang IW, Makishima Y, Kato T, Park S, Terzic A and Park EY: Human acetyl-CoA carboxylase 2 expressed in silkworm Bombyx mori exhibits posttranslational biotinylation and phosphorylation. Appl Microbiol Biotechnol. 98:8201–8209. 2014. View Article : Google Scholar :
20	Yan H, Li Y, Wang C, Zhang Y, Liu C, Zhou K and Hua Y: Contrary microRNA expression pattern between fetal and adult cardiac remodeling: Therapeutic value for heart failure. Cardiovasc Toxicol. 17:267–276. 2017. View Article : Google Scholar
21	Salvador AM, Nevers T, Velázquez F, Aronovitz M, Wang B, Molina Abadía A, Jaffe IZ, Karas RH, Blanton RM and Alcaide P: Intercellular adhesion molecule 1 regulates left ventricular leukocyte infiltration, cardiac remodeling, and function in pressure overload-induced heart failure. J Am Heart Assoc. 5:e0031262016. View Article : Google Scholar :
22	Kapoun AM, Liang F, O'young G, Damm DL, Quon D, White RT, Munson K, Lam A, Schreiner GF and Protter AA: B-Type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts, myofibroblast conversion, proliferation, and inflammation. Circ Res. 94:453–461. 2004. View Article : Google Scholar
23	Akula MK, Shi M, Jiang Z, Foster CE, Miao D, Li AS, Zhang X, Gavin RM, Forde SD, Germain G, et al: Control of the innate immune response by the mevalonate pathway. Nat Immunol. 17:922–929. 2016. View Article : Google Scholar :
24	Bönner F, Borg N, Jacoby C, Temme S, Ding Z, Flögel U and Schrader J: Ecto-5′-nucleotidase on immune cells protects from adverse cardiac remodeling. Circ Res. 113:301–312. 2013. View Article : Google Scholar
25	Stych B: Regulation and role of RNA Pol II CTD phosphorylation in the transcription cycle of the Nos2 gene (unpublished PhD thesis). University of Vienna. 2014.
26	Sun J, Shi YH, Le GW and Ma XY: Distinct immune response induced by peptidoglycan derived from lactobacillus sp. World J Gastroenterol. 11:6330–6337. 2005. View Article : Google Scholar :
27	Zheng B, Cao LS, Zeng QT, Wang X, Li DZ and Liao YH: Inhibition of NOS2 ameliorates cardiac remodeling, improves heart function after myocardial infarction in rats. Basic Res Cardiol. 99:264–271. 2004. View Article : Google Scholar
28	Kempf T and Wollert KC: Nitric oxide and the enigma of cardiac hypertrophy. Bioessays. 26:608–615. 2004. View Article : Google Scholar
29	Liao Y, Zhao H, Ogai A, Kato H, Asakura M, Kim J, Asanuma H, Minamino T, Takashima S and Kitakaze M: Atorvastatin slows the progression of cardiac remodeling in mice with pressure overload and inhibits epidermal growth factor receptor activation. Hypertens Res. 31:335–344. 2008. View Article : Google Scholar
30	Szalay G, Sauter M, Haberland M, Zuegel U, Steinmeyer A, Kandolf R and Klingel K: Osteopontin: A fibrosis-related marker molecule in cardiac remodeling of enterovirus myocarditis in the susceptible host. Circ Res. 104:851–859. 2009. View Article : Google Scholar
31	Batchu SN, Hughson A, Gerloff J, Fowell DJ and Korshunov VA: Role of Axl in early kidney inflammation and progression of salt-dependent hypertension. Hypertension. 62:302–309. 2013. View Article : Google Scholar
32	Han YL, Li YL, Jia LX, Cheng JZ, Qi YF, Zhang HJ and Du J: Reciprocal interaction between macrophages and T cells stimulates IFN-γ and MCP-1 production in Ang II-induced cardiac inflammation and fibrosis. PLoS One. 7:e355062012. View Article : Google Scholar :
33	Arandjelovic S and Ravichandran KS: A MERry response after myocardial infarction. Circ Res. 113:949–951. 2013. View Article : Google Scholar :
34	Zhang Y, Sivakumaran P, Newcomb AE, Hernandez D, Harris N, Khanabdali R, Liu GS, Kelly DJ, Pébay A, Hewitt AW, et al: Cardiac repair with a novel population of mesenchymal stem cells resident in the human heart. Stem Cells. 33:3100–3113. 2015. View Article : Google Scholar