Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis Via Repression of Proangiogenic Factors

Overview

Journal Arthritis Rheumatol

Publisher Wiley

Specialty Rheumatology

Date 2016 Aug 3

PMID 27482699

Citations 32

Authors

Pei-Suen Tsou

Jonathan D Wren

M Asif Amin

Elena Schiopu

David A Fox

Dinesh Khanna

Amr H Sawalha

Affiliations

Soon will be listed here.

Abstract

Objective: Vascular dysfunction represents a disease-initiating event in systemic sclerosis (SSc; scleroderma). Results of recent studies suggest that epigenetic dysregulation impairs normal angiogenesis and can result in abnormal patterns of blood vessel growth. Histone deacetylases (HDACs) control endothelial cell (EC) proliferation and regulate EC migration. Specifically, HDAC-5 appears to be antiangiogenic. This study was undertaken to test whether HDAC-5 contributes to impaired angiogenesis in SSc by repressing proangiogenic factors in ECs.

Methods: Dermal ECs were isolated from patients with diffuse cutaneous SSc and healthy controls. Angiogenesis was assessed using an in vitro Matrigel tube formation assay. An assay for transposase-accessible chromatin using sequencing (ATAC-seq) was performed to assess and localize the genome-wide effects of HDAC5 knockdown on chromatin accessibility.

Results: The expression of HDAC5 was significantly increased in ECs from patients with SSc compared to healthy control ECs. Silencing of HDAC5 in SSc ECs restored normal angiogenesis. HDAC5 knockdown followed by ATAC-seq assay in SSc ECs identified key HDAC5-regulated genes involved in angiogenesis and fibrosis, such as CYR61, PVRL2, and FSTL1. Simultaneous knockdown of HDAC5 in conjunction with either CYR61, PVRL2, or FSTL1 inhibited angiogenesis in SSc ECs. Conversely, overexpression of these genes individually led to an increase in tube formation as assessed by Matrigel assay, suggesting that these genes play functional roles in the impairment of angiogenesis in SSc.

Conclusion: Several novel HDAC5-regulated target genes associated with impaired angiogenesis were identified in SSc ECs by ATAC-seq. The results of this study provide a potential link between epigenetic regulation and impaired angiogenesis in SSc, and identify a novel mechanism for the dysregulated angiogenesis that characterizes this disease.

Citing Articles

Recent Insights into the Role of DNA Methylation and Histone Modifications in Systemic Sclerosis: A Scoping Review.

Kostova T, Karalilova R, Batalov Z, Kazakova M, Sarafian V, Batalov A Diagnostics (Basel). 2024; 14(6).

PMID: 38535072 PMC: 10969595. DOI: 10.3390/diagnostics14060652.

Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology.

Patil R, Maloney M, Lucas R, Fulton D, Patel V, Bagi Z Biomolecules. 2024; 14(2).

PMID: 38397377 PMC: 10886568. DOI: 10.3390/biom14020140.

induces the transcriptional activity of host YAP in a Hippo-independent fashion.

Caven L, Brinkworth A, Carabeo R Front Cell Infect Microbiol. 2023; 13:1098420.

PMID: 36923592 PMC: 10008951. DOI: 10.3389/fcimb.2023.1098420.

The critical importance of epigenetics in autoimmune-related skin diseases.

Gao L, Lu Q Front Med. 2023; 17(1):43-57.

PMID: 36811762 DOI: 10.1007/s11684-022-0980-8.

HDAC5-mediated Smad7 silencing through MEF2A is critical for fibroblast activation and hypertrophic scar formation.

Gao Y, Liu Y, Zheng D, Ho C, Wen D, Sun J Int J Biol Sci. 2022; 18(15):5724-5739.

PMID: 36263180 PMC: 9576526. DOI: 10.7150/ijbs.76140.

References

Tsou P, Amin M, Campbell P, Zakhem G, Balogh B, Edhayan G . Activation of the Thromboxane A2 Receptor by 8-Isoprostane Inhibits the Pro-Angiogenic Effect of Vascular Endothelial Growth Factor in Scleroderma. J Invest Dermatol. 2015; 135(12):3153-3162. PMC: 4648660. DOI: 10.1038/jid.2015.323. View

Tsou P, Rabquer B, Ohara R, Stinson W, Campbell P, Amin M . Scleroderma dermal microvascular endothelial cells exhibit defective response to pro-angiogenic chemokines. Rheumatology (Oxford). 2015; 55(4):745-54. PMC: 5009475. DOI: 10.1093/rheumatology/kev399. View

Wankell M, Kaesler S, Zhang Y, Florence C, Werner S, Duan R . The activin binding proteins follistatin and follistatin-related protein are differentially regulated in vitro and during cutaneous wound repair. J Endocrinol. 2001; 171(3):385-95. DOI: 10.1677/joe.0.1710385. View

Romano E, Chora I, Manetti M, Mazzotta C, Rosa I, Bellando-Randone S . Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis. Ann Rheum Dis. 2015; 75(8):1541-9. DOI: 10.1136/annrheumdis-2015-207483. View

Mazzotta C, Romano E, Bruni C, Manetti M, Lepri G, Bellando-Randone S . Plexin-D1/Semaphorin 3E pathway may contribute to dysregulation of vascular tone control and defective angiogenesis in systemic sclerosis. Arthritis Res Ther. 2015; 17:221. PMC: 4546224. DOI: 10.1186/s13075-015-0749-4. View

Kim K, Chen C, Monzon R, Lau L . Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol. 2013; 33(10):2078-90. PMC: 3647960. DOI: 10.1128/MCB.00049-13. View

Fukuhara A, Irie K, Nakanishi H, Takekuni K, Kawakatsu T, Ikeda W . Involvement of nectin in the localization of junctional adhesion molecule at tight junctions. Oncogene. 2002; 21(50):7642-55. DOI: 10.1038/sj.onc.1205875. View

Tawa H, Rikitake Y, Takahashi M, Amano H, Miyata M, Satomi-Kobayashi S . Role of afadin in vascular endothelial growth factor- and sphingosine 1-phosphate-induced angiogenesis. Circ Res. 2010; 106(11):1731-42. DOI: 10.1161/CIRCRESAHA.110.216747. View

Deroanne C, Bonjean K, Servotte S, Devy L, Colige A, Clausse N . Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene. 2002; 21(3):427-36. DOI: 10.1038/sj.onc.1205108. View

10.

Li D, Wang Y, Xu N, Wei Q, Wu M, Li X . Follistatin-like protein 1 is elevated in systemic autoimmune diseases and correlated with disease activity in patients with rheumatoid arthritis. Arthritis Res Ther. 2011; 13(1):R17. PMC: 3241361. DOI: 10.1186/ar3241. View

11.

Wang Y, Fan P, Kahaleh B . Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum. 2006; 54(7):2271-9. DOI: 10.1002/art.21948. View

12.

Saigusa R, Asano Y, Taniguchi T, Yamashita T, Takahashi T, Ichimura Y . A possible contribution of endothelial CCN1 downregulation due to Fli1 deficiency to the development of digital ulcers in systemic sclerosis. Exp Dermatol. 2014; 24(2):127-32. DOI: 10.1111/exd.12602. View

13.

Del Principe D, Lista P, Malorni W, Giammarioli A . Fibroblast autophagy in fibrotic disorders. J Pathol. 2012; 229(2):208-20. DOI: 10.1002/path.4115. View

14.

Poralla L, Stroh T, Erben U, Sittig M, Liebig S, Siegmund B . Histone deacetylase 5 regulates the inflammatory response of macrophages. J Cell Mol Med. 2015; 19(9):2162-71. PMC: 4568921. DOI: 10.1111/jcmm.12595. View

15.

Panse K, Felkin L, Lopez-Olaneta M, Gomez-Salinero J, Villalba M, Munoz L . Follistatin-like 3 mediates paracrine fibroblast activation by cardiomyocytes. J Cardiovasc Transl Res. 2012; 5(6):814-26. DOI: 10.1007/s12265-012-9400-9. View

16.

. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012; 489(7414):57-74. PMC: 3439153. DOI: 10.1038/nature11247. View

17.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

18.

Manetti M, Guiducci S, Romano E, Ceccarelli C, Bellando-Randone S, Conforti M . Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis. Circ Res. 2011; 109(3):e14-26. DOI: 10.1161/CIRCRESAHA.111.242057. View

19.

Wren J, Garner H . Shared relationship analysis: ranking set cohesion and commonalities within a literature-derived relationship network. Bioinformatics. 2004; 20(2):191-8. DOI: 10.1093/bioinformatics/btg390. View

20.

Zhang Y, Liu T, Meyer C, Eeckhoute J, Johnson D, Bernstein B . Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008; 9(9):R137. PMC: 2592715. DOI: 10.1186/gb-2008-9-9-r137. View