Histone deacetylase inhibition disturbs the balance between ACE and chymase expression in endothelial cells: a potential mechanism of chymase activation in preeclampsia

Article metrics

Abstract

Chymase is a major angiotensin-converting enzyme (ACE)-independent angiotensin convertase, and its expression is upregulated in the maternal vascular endothelium in preeclampsia, a hypertensive disorder in human pregnancy. Increased chymase-dependent angiotensin II generation has been reported in several cardiovascular diseases, including atherosclerosis and aneurysmal lesions. However, it remains unclear how chymase is activated. Histone modification is an important regulatory mechanism that controls gene expression. In this study, using a chymase overexpression cell model, we investigated the mechanisms of chymase activation to test our hypothesis that histone acetylation could promote endothelial chymase expression. Human umbilical vein endothelial cells were transfected with the chymase gene. Trichostatin A was used to inhibit histone deacetylases (HDACs). The expression levels of chymase, ACE, and HDACs were determined by western blotting. Our results showed that ACE was strongly expressed in control cells, but was significantly downregulated in cells transfected to express chymase. Strikingly, we also found that HDAC inhibition resulted in a dose-dependent increase in chymase expression but a dose-dependent decrease in ACE expression in cells transfected with the chymase gene. HDAC inhibition was confirmed by the decreased expression of HDAC1 and HDAC6 in cells treated with trichostatin A. Increased chymase expression associated with reduced histone deacetylase expression was further confirmed by immunostaining of subcutaneous adipose sections from women with preeclampsia. We conclude that aberrant HDAC expression/activity could disturb the balance between ACE and chymase expression in endothelial cells. Our results support the clinical importance of chymase as a new pharmacological target for cardiovascular disorders.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet. 2007;369:1208–19.

  2. 2.

    Bacani C, Frishman WH. Chymase: a new pharmacologic target in cardiovascular disease. Cardiol Rev. 2006;14:187–93.

  3. 3.

    Kelley JL, Chi DS, Abou-Auda W, Smith JK, Krishnaswamy G. The molecular role of mast cells in atherosclerotic cardiovascular disease. Mol Med Today. 2000;6:304–8.

  4. 4.

    Cristovam PC, Carmona AK, Arnoni CP, Maquigussa E, Pereira LG, Boim MA. Role of chymase in diabetic nephropathy. Exp Biol Med (Maywood). 2012;237:985–92.

  5. 5.

    Wu Q, Kuo HC, Deng GG. Serine proteases and cardiac function. Biochim Biophys Acta. 2005;1751:82–94.

  6. 6.

    Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem. 1990;265:22348–57.

  7. 7.

    Richard V, Hurel-Merle S, Scalbert E, Ferry G, Lallemand F, Bessou JP et al. Functional evidence for a role of vascular chymase in the production of angiotensin II in isolated human arteries. Circulation. 2001;104:750–2.

  8. 8.

    Nakano A, Kishi F, Minami K, Wakabayashi H, Nakaya Y, Kido H. Selective conversion of big endothelins to tracheal smooth muscle-constricting 31-amino acid-length endothelins by chymase from human mast cells. J Immunol. 1997;159:1987–92.

  9. 9.

    Ihara M, Urata H, Kinoshita A, Suzumiya J, Sasaguri M, Kikuchi M et al. Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. Hypertension. 1999;33:1399–405.

  10. 10.

    Wang Y, Gu Y, Lewis DF, Alexander JS, Granger DN. Elevated plasma chymotrypsin-like protease (chymase) activity in women with preeclampsia. Hypertens Pregn. 2010;29:253–61.

  11. 11.

    Gu Y, Lewis DF, Alexander JS, Wang Y. Upregulation of cathepsin C expression contributes to endothelial chymase activation in preeclampsia. Hypertens Res. 2017;40:976–81.

  12. 12.

    Wang T, Han SX, Zhang SF, Ning YY, Chen L, Chen YJ et al. Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters. Respir Res. 2010;11:36

  13. 13.

    Furubayashi K, Takai S, Jin D, Muramatsu M, Ibaraki T, Nishimoto M et al. The significance of chymase in the progression of abdominal aortic aneurysms in dogs. Hypertens Res. 2016;30:349–57.

  14. 14.

    Devarajan S, Yahiro E, Uehara Y, Habe S, Nishiyama A, Miura S et al. Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension. Am J Physiol Heart Circ Physiol. 2015;309:H1987–H1996.

  15. 15.

    Wang Y, Adair CD, Coe L, Weeks JW, Lewis DF, Alexander JS. Activation of endothelial cells in preeclampsia: increased neutrophil-endothelial adhesion correlates with up-regulation of adhesion molecule P-selectin in human umbilical vein endothelial cells isolated from preeclampsia. J Soc Gynecol Investig. 1998;5:237–43.

  16. 16.

    Gu Y, Liu C, Alexander JS, Groome LJ, Wang Y. Chymotrypsin-like protease (chymase) mediates endothelial activation by factors derived from preeclamptic placentas. Reprod Sci. 2009;16:905–13.

  17. 17.

    Batlle M, Roig E, Perez-Villa F, Lario S, Cejudo-Martin P, Garcia-Pras E et al. Increased expression of the renin-angiotensin system and mast cell density but not of angiotensin-converting enzyme II in late stages of human heart failure. J Heart Lung Transplant. 2006;25:1117–25.

  18. 18.

    Huang XR, Chen WY, Truong LD, Lan HY. Chymase is upregulated in diabetic nephropathy: implications for an alternative pathway of angiotensin II-mediated diabetic renal and vascular disease. J Am Soc Nephrol. 2003;14:1738–47.

  19. 19.

    Pfeufer A, Osterziel KJ, Urata H, Borck G, Schuster H, Wienker T et al. Angiotensin-converting enzyme and heart chymase gene polymorphisms in hypertrophic cardiomyopathy. Am J Cardiol. 1996;78:362–4.

  20. 20.

    Mizutani H, Schechter N, Lazarus G, Black RA, Kupper TS. Rapid and specific conversion of precursor interleukin 1 beta (IL-1 beta) to an active IL-1 species by human mast cell chymase. J Exp Med. 1991;174:821–5.

  21. 21.

    Taipale J, Lohi J, Saarinen J, Kovanen PT, Keski-Oja J. Human mast cell chymase and leukocyte elastase release latent transforming growth factor-beta 1 from the extracellular matrix of cultured human epithelial and endothelial cells. J Biol Chem. 1995;270:4689–96.

  22. 22.

    Tchougounova E, Lundequist A, Fajardo I, Winberg JO, Abrink M, Pejler G. A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem. 2005;280:9291–6.

  23. 23.

    Lee M, Sommerhoff CP, von Eckardstein A, Zettl F, Fritz H, Kovanen PT. Mast cell tryptase degrades HDL and blocks its function as an acceptor of cellular cholesterol. Arterioscler Thromb Vasc Biol. 2002;22:2086–91.

  24. 24.

    Lee M, Calabresi L, Chiesa G, Franceschini G, Kovanen PT. Mast cell chymase degrades apoE and apoA-II in apoA-I-knockout mouse plasma and reduces its ability to promote cellular cholesterol efflux. Arterioscler Thromb Vasc Biol. 2002;22:1475–81.

  25. 25.

    Koka V, Wang W, Huang XR, Kim-Mitsuyama S, Truong LD, Lan HY. Advanced glycation end products activate a chymase-dependent angiotensin II-generating pathway in diabetic complications. Circulation. 2006;113:1353–60.

  26. 26.

    Wang Y, Gu Y, Lewis DF. Endothelial angiotensin II generation induced by placenta-derived factors from preeclampsia. Reprod Sci. 2008;15:932–8.

  27. 27.

    Patra N, De U, Kim TH, Lee YJ, Ahn MY, Kim ND et al. A novel histone deacetylase (HDAC) inhibitor MHY219 induces apoptosis via up-regulation of androgen receptor expression in human prostate cancer cells. Biomed Pharmacother. 2013;67:407–15.

  28. 28.

    Uehara Y, Urata H, Sasaguri M, Ideishi M, Sakata N, Tashiro T et al. Increased chymase activity in internal thoracic artery of patients with hypercholesterolemia. Hypertension. 2000;35(1 Pt 1):55–60.

  29. 29.

    Takai S, Sakaguchi M, Jin D, Yamada M, Kirimura K, Miyazaki M. Different angiotensin II-forming pathways in human and rat vascular tissues. Clin Chim Acta. 2001;305:191–5.

  30. 30.

    Takai S, Shiota N, Jin D, Miyazaki M. Functional role of chymase in angiotensin II formation in human vascular tissue. J Cardiovasc Pharmacol. 1998;32:826–33.

  31. 31.

    Froogh G, Pinto JT, Le Y, Kandhi S, Aleligne Y, Huang A et al. Chymase-dependent production of angiotensin II: an old enzyme in old hearts. Am J Physiol Heart Circ Physiol. 2017;312:H223–H231.

  32. 32.

    Wang Y, Lewis DF, Gu Y, Zhao S, Groome LJ. Elevated maternal soluble gp130 and IL-6 levels and reduced gp130 and SOCS-3 expressions in women with preeclampsia. Hypertension. 2011;57:336–42.

  33. 33.

    Wang Y, Dong Q, Gu Y, Groome LJ. Up-regulation of miR-203 expression induces endothelial inflammatory response: potential role in preeclampsia. Am J Reprod Immunol. 2016;76:482–90.

  34. 34.

    Gu Y, Lewis DF, Deere K, Groome LJ, Wang Y. Elevated maternal IL-16 levels, enhanced IL-16 expressions in endothelium and leukocytes, and increased IL-16 production by placental trophoblasts in women with preeclampsia. J Immunol. 2008;181:4418–22.

  35. 35.

    van de Wal RM, Plokker HW, Lok DJ, Boomsma F, van der Horst FA, van Veldhuisen DJ et al. Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition. Int J Cardiol. 2006;106:367–72.

  36. 36.

    Chrysant SG. Current status of dual renin angiotensin aldosterone system blockade for the treatment of cardiovascular diseases. Am J Cardiol. 2010;105:849–52.

  37. 37.

    Takato H, Yasui M, Ichikawa Y, Waseda Y, Inuzuka K, Nishizawa Y et al. The specific chymase inhibitor TY-51469 suppresses the accumulation of neutrophils in the lung and reduces silica-induced pulmonary fibrosis in mice. Exp Lung Res. 2011;37:101–8.

  38. 38.

    Pejler G, Rönnberg E, Waern I, Wernersson S. Mast cell proteases- multifaceted regulators of inflammatory disease. Blood. 2010;115:4981–90.

  39. 39.

    Wang Y, Zhang Y, Lewis DF, Gu Y, Li H, Granger DN et al. Protease chymotrypsin mediates the endothelial expression of P- and E-selectin, but not ICAM and VCAM, induced by placental trophoblasts from preeclamptic pregnancies. Placenta. 2003;24:851–61.

Download references

Acknowledgements

This study was supported by a grant from the National Institutes of Health NICHD R21HD076289 to Yuping Wang.

Author information

Correspondence to Yuping Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

  • chymase
  • ACE
  • HDAC
  • endothelial cells
  • preeclampsia