Discoidin domain Receptor 2: A determinant of metabolic syndrome-associated arterial fibrosis in non-human primates

Autoři: Mereena George Ushakumary aff001;  Mingyi Wang aff002;  Harikrishnan V aff001;  Allen Sam Titus aff001;  Jing Zhang aff002;  Lijuan Liu aff002;  Robert Monticone aff002;  Yushi Wang aff002;  Julie A. Mattison aff004;  Rafael de Cabo aff004;  Edward G. Lakatta aff002;  Shivakumar Kailasam aff001
Působiště autorů: Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India aff001;  Laboratory of Cardiovascular Science, National Institute on Aging, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America aff002;  Department of Cardiology, The First Hospital of Jilin University, Changchun, China aff003;  Translational Gerontology Branch, National Institute on Aging, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0225911


Collagen accumulation and remodeling in the vascular wall is a cardinal feature of vascular fibrosis that exacerbates the complications of hypertension, aging, diabetes and atherosclerosis. With no specific therapy available to date, identification of mechanisms underlying vascular fibrogenesis is an important clinical goal. Here, we tested the hypothesis that Discoidin Domain Receptor 2 (DDR2), a collagen-specific receptor tyrosine kinase, is a determinant of arterial fibrosis. We report a significant increase in collagen type 1 levels along with collagen and ECM remodeling, degradation of elastic laminae, enhanced fat deposition and calcification in the abdominal aorta in a non-human primate model of high-fat, high-sucrose diet (HFS)-induced metabolic syndrome. These changes were associated with a marked increase in DDR2. Resveratrol attenuated collagen type I deposition and remodeling induced by the HFS diet, with a concomintant reduction in DDR2. Further, in isolated rat vascular adventitial fibroblasts and VSMCs, hyperglycemia increased DDR2 and collagen type I expression via TGF-β1/SMAD2/3, which was attenuated by resveratrol. Notably, gene knockdown and overexpression approaches demonstrated an obligate role for DDR2 in hyperglycemia-induced increase in collagen type I expression in these cells. Together, our observations point to DDR2 as a hitherto unrecognized molecular link between metabolic syndrome and arterial fibrosis, and hence a therapeutic target.

Klíčová slova:

Analysis of variance – Collagens – Diet – Fibroblasts – Fibrosis – Gene expression – Monkeys – Protein expression


1. Myofibroblast-Mediated Adventitial Remodeling | Arteriosclerosis, Thrombosis, and Vascular Biology [Internet]. [cited 2019 May 28]. https://www.ahajournals.org/doi/10.1161/ATVBAHA.111.231548

2. Schillaci G, Pirro M, Vaudo G, Mannarino MR, Savarese G, Pucci G, et al. Metabolic syndrome is associated with aortic stiffness in untreated essential hypertension. Hypertension. 2005 Jun;45(6):1078–82. doi: 10.1161/01.HYP.0000165313.84007.7d 15867139

3. AlGhatrif M, Strait JB, Morrell CH, Canepa M, Wright J, Elango P, et al. Longitudinal trajectories of arterial stiffness and the role of blood pressure: the Baltimore Longitudinal Study of Aging. Hypertension. 2013 Nov;62(5):934–41. doi: 10.1161/HYPERTENSIONAHA.113.01445 24001897

4. Selvin E, Najjar SS, Cornish TC, Halushka MK. A comprehensive histopathological evaluation of vascular medial fibrosis: Insights into the pathophysiology of arterial stiffening. Atherosclerosis. 2010 Jan 1;208(1):69–74. doi: 10.1016/j.atherosclerosis.2009.06.025 19632677

5. Sun Z. Aging, Arterial Stiffness and Hypertension. Hypertension. 2015 Feb;65(2):252–6. doi: 10.1161/HYPERTENSIONAHA.114.03617 25368028

6. Xu M, Huang Y, Xie L, Peng K, Ding L, Lin L, et al. Diabetes and Risk of Arterial Stiffness: A Mendelian Randomization Analysis. Diabetes. 2016 Jun;65(6):1731–40. doi: 10.2337/db15-1533 26953161

7. Xu J, Shi G-P. Vascular wall extracellular matrix proteins and vascular diseases. Biochim Biophys Acta. 2014 Nov;1842(11):2106–19. doi: 10.1016/j.bbadis.2014.07.008 25045854

8. Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, et al. Inflammation and Mechanical Stretch Promote Aortic Stiffening in Hypertension Through Activation of p38 Mitogen-Activated Protein KinaseNovelty and Significance. Circulation Research. 2014 Feb 14;114(4):616–25. doi: 10.1161/CIRCRESAHA.114.302157 24347665

9. Harvey A, Montezano AC, Lopes RA, Rios F, Touyz RM. Vascular Fibrosis in Aging and Hypertension: Molecular Mechanisms and Clinical Implications. Can J Cardiol. 2016 May;32(5):659–68. doi: 10.1016/j.cjca.2016.02.070 27118293

10. Lee SJ, Bae SS, Kim KH, Lee WS, Rhim BY, Hong KW, et al. High glucose enhances MMP-2 production in adventitial fibroblasts via Akt1-dependent NF-κB pathway. FEBS Letters. 2007 Sep 4;581(22):4189–94. doi: 10.1016/j.febslet.2007.07.058 17692316

11. Versari D, Gossl M, Mannheim D, Daghini E, Galili O, Napoli C, et al. Hypertension and hypercholesterolemia differentially affect the function and structure of pig carotid artery. Hypertension. 2007 Dec;50(6):1063–8. doi: 10.1161/HYPERTENSIONAHA.107.093260 17968002

12. Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012 Sep 5;308(9):875–81. doi: 10.1001/2012.jama.10503 22948697

13. Raaz U, Schellinger IN, Chernogubova E, Warnecke C, Kayama Y, Penov K, et al. Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes. Circ Res. 2015 Aug 28;117(6):513–24. doi: 10.1161/CIRCRESAHA.115.306341 26208651

14. Ponticos M, Smith BD. Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis. J Biomed Res. 2014 Jan;28(1):25–39. doi: 10.7555/JBR.27.20130064 24474961

15. Vogel W, Gish GD, Alves F, Pawson T. The Discoidin Domain Receptor Tyrosine Kinases Are Activated by Collagen. Molecular Cell. 1997 Dec 1;1(1):13–23. doi: 10.1016/s1097-2765(00)80003-9 9659899

16. Olaso E, Lin H-C, Wang L-H, Friedman SL. Impaired dermal wound healing in discoidin domain receptor 2-deficient mice associated with defective extracellular matrix remodeling. Fibrogenesis Tissue Repair. 2011 Feb 2;4(1):5. doi: 10.1186/1755-1536-4-5 21288331

17. Jia S, Agarwal M, Yang J, Horowitz JC, White ES, Kim KK. Discoidin Domain Receptor 2 Signaling Regulates Fibroblast Apoptosis through PDK1/Akt. Am J Respir Cell Mol Biol. 2018;59(3):295–305. doi: 10.1165/rcmb.2017-0419OC 29652518

18. Olaso E, Ikeda K, Eng FJ, Xu L, Wang LH, Lin HC, et al. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest. 2001 Nov;108(9):1369–78. doi: 10.1172/JCI12373 11696582

19. Kim D, You E, Jeong J, Ko P, Kim J-W, Rhee S. DDR2 controls the epithelial-mesenchymal-transition-related gene expression via c-Myb acetylation upon matrix stiffening. Sci Rep. 2017 28;7(1):6847. doi: 10.1038/s41598-017-07126-7 28754957

20. Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al. Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis. Mol Ther. 2016;24(10):1734–44. doi: 10.1038/mt.2016.109 27350126

21. Mattison JA, Wang M, Bernier M, Zhang J, Park S-S, Maudsley S, et al. Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab. 2014 Jul 1;20(1):183–90. doi: 10.1016/j.cmet.2014.04.018 24882067

22. Pauly RR, Bilato C, Cheng L, Monticone R, Crow MT. Vascular smooth muscle cell cultures. METHCELL BIOL. 1997;(52):133–54.

23. Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK. Reactive Oxygen Species in Metabolic and Inflammatory Signaling. Circ Res. 2018 Mar 16;122(6):877–902. doi: 10.1161/CIRCRESAHA.117.311401 29700084

24. George M, Vijayakumar A, Dhanesh SB, James J, Shivakumar K. Molecular basis and functional significance of Angiotensin II-induced increase in Discoidin Domain Receptor 2 gene expression in cardiac fibroblasts. Journal of Molecular and Cellular Cardiology. 2016 Jan 1;90:59–69. doi: 10.1016/j.yjmcc.2015.12.004 26674152

25. Wang M, Kim SH, Monticone RE, Lakatta EG. Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis. Hypertension. 2015 Apr;65(4):698–703. doi: 10.1161/HYPERTENSIONAHA.114.03618 25667214

26. Hou G, Vogel W, Bendeck MP. The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. J Clin Invest. 2001 Mar;107(6):727–35. doi: 10.1172/JCI10720 11254672

27. Franco C, Hou G, Ahmad PJ, Fu EYK, Koh L, Vogel WF, et al. Discoidin domain receptor 1 (ddr1) deletion decreases atherosclerosis by accelerating matrix accumulation and reducing inflammation in low-density lipoprotein receptor-deficient mice. Circ Res. 2008 May 23;102(10):1202–11. doi: 10.1161/CIRCRESAHA.107.170662 18451340

28. Chen S-C, Wang B-W, Wang DL, Shyu K-G. Hypoxia induces discoidin domain receptor-2 expression via the p38 pathway in vascular smooth muscle cells to increase their migration. Biochem Biophys Res Commun. 2008 Oct 3;374(4):662–7. doi: 10.1016/j.bbrc.2008.07.092 18664364

29. Ferri N, Carragher NO, Raines EW. Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling: potential implications in atherosclerosis and lymphangioleiomyomatosis. Am J Pathol. 2004 May;164(5):1575–85. doi: 10.1016/S0002-9440(10)63716-9 15111304

30. Hou G, Wang D, Bendeck MP. Deletion of discoidin domain receptor 2 does not affect smooth muscle cell adhesion, migration, or proliferation in response to type I collagen. Cardiovasc Pathol. 2012 Jun;21(3):214–8. doi: 10.1016/j.carpath.2011.07.006 21865059

31. Lavrentyev EN, Estes AM, Malik KU. Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells. Circ Res. 2007 Aug 31;101(5):455–64. doi: 10.1161/CIRCRESAHA.107.151852 17626897

32. Li JH, Huang XR, Zhu H-J, Johnson R, Lan HY. Role of TGF-β signaling in extracellular matrix production under high glucose conditions. Kidney International. 2003 Jun 1;63(6):2010–9. doi: 10.1046/j.1523-1755.2003.00016.x 12753288

33. Szkudelski T, Szkudelska K. Resveratrol and diabetes: from animal to human studies. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease. 2015 Jun 1;1852(6):1145–54.

34. Berman AY, Motechin RA, Wiesenfeld MY, Holz MK. The therapeutic potential of resveratrol: a review of clinical trials. npj Precision Onc. 2017 Sep 25;1(1):1–9.

35. Mizutani K, Ikeda K, Yamori Y. Resveratrol inhibits AGEs-induced proliferation and collagen synthesis activity in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. Biochem Biophys Res Commun. 2000 Jul 21;274(1):61–7. doi: 10.1006/bbrc.2000.3097 10903896

36. Kessoku T, Imajo K, Honda Y, Kato T, Ogawa Y, Tomeno W, et al. Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci Rep. 2016 Feb 25;6:22251. doi: 10.1038/srep22251 26911834

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2019 Číslo 12
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