Skip to main content

Advertisement

SpringerLink
Log in

Effect of PAR2 in regulating TNF-α and NAD(P)H oxidase in coronary arterioles in type 2 diabetic mice

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Protease-activated receptor-2 (PAR2) is expressed in endothelial cells and mediates endothelium-dependent vasodilation. We hypothesized that PAR2 regulates tumor necrosis factor-alpha (TNF-α)-induced coronary arteriolar dysfunction in type 2 diabetic (db/db) mice. To test this, coronary arterioles from WT control, db/db, db/db mice treated with PAR2 antagonist FSLLRY–NH2 (db/db+FSLLRY–NH2) and db/db mice null for TNF (dbTNF−/dbTNF−) were isolated and pressurized (60 cmH2O) without flow. Although vasodilation to the endothelium-independent vasodilator sodium nitroprusside (SNP) was not different among WT, db/db, db/db+FSLLRY–NH2 and dbTNF−/dbTNF−, endothelium-dependent acetylcholine (ACh)- and flow-mediated vasodilation were impaired in db/db mice but were enhanced in dbTNF−/dbTNF− mice and db/db mice treated with PAR2 antagonist. NOS inhibitor N G-nitro-l-arginine-methyl ester (l-NAME) significantly reduced ACh-induced dilation in WT, dbTNF−/dbTNF− and db/db+FSLLRY–NH2, but did not alter the vasodilation in db/db mice. In contrast, cyclooxygenase (COX) inhibitor indomethacin (Indo) did not alter ACh-induced vasodilation in these four groups of mice. PAR2-activating peptide (PAR2-AP, 2-Furoyl-LIGRLO-am)-induced dilation was higher in db/db mice than that in WT, dbTNF−/dbTNF− and db/db mice treated with PAR2 antagonist. These effects were abolished by denudation, or in the presence of l-NAME or Indo. Protein expressions of TNF-α, PAR2, gp91phox and p47phox in the heart and isolated coronary arterioles were higher in db/db mice compared to WT mice. Administration of PAR2 antagonist to db/db mice reduced protein expression of TNF-α, gp91phox and PAR2. Protein expression of gp91phox and p47phox was lower in dbTNF−/dbTNF− compared to db/db mice. These results indicate that PAR2 plays a pivotal role in endothelial dysfunction in type 2 diabetes by up-regulating the expression/production of TNF-α and activating NAD(P)H oxidase subunit p47phox.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Atsufumi K, Ryotaro K, Takeshi M, Kazuo K, Mamoru T (1998) Increased vascular permeability by a specific agonist of protease-activated receptor-2 in rat hindpaw. Br J Pharmacol 125:419–422

    Article  Google Scholar 

  2. Banfi C, Brioschi M, Barbieri SS, Eligini S, Barcella S, Tremoli E, Colli S, Mussoni L (2009) Mitochondrial reactive oxygen species: a common pathway for PAR1- and PAR2-mediated tissue factor induction in human endothelial cells. J Thromb Haemost 7:206–216

    Article  CAS  PubMed  Google Scholar 

  3. Bramos D, Ikonomidis I, Tsirikos N, Kottis G, Kostopoulou V, Pamboucas C, Papadopoulou E, Venetsanou K, Giatrakos N, Yang GZ, Nihoyannopoulos P, Toumanidis S (2008) The association of coronary flow changes and inflammatory indices to ischaemia–reperfusion microvascular damage and left ventricular remodeling. Basic Res Cardiol 103:345–355

    Article  CAS  PubMed  Google Scholar 

  4. Chappell D, Hofmann-Kiefer K, Jacob K, Rehm M, Briegel J, Welsch U, Conzen P, Becker BF (2009) TNF-α induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol 104:78–89

    Article  CAS  PubMed  Google Scholar 

  5. Cicala C (2002) Protease activated receptor 2 and the cardiovascular system. Br J Pharmacol 135:14–20

    Article  CAS  PubMed  Google Scholar 

  6. Cicala C, Pinto A, Bucci M, Sorrentino R, Walker B, Harriot P, Cruchley A, Kapas S, Howells GL, Cirino G (1999) Protease-activated receptor-2 involvement in hypotension in normal and endotoxemic rats in vivo. Circulation 99:2590–2597

    CAS  PubMed  Google Scholar 

  7. Cocks TM, Moffatt JD (2000) Protease-activated receptors: sentries for inflammation? Trends Pharmacol Sci 21:103–108

    Article  CAS  PubMed  Google Scholar 

  8. D’Andrea MR, Derian CK, Leturcq D, Baker SM, Brunmark A, Ling P, Darrow AL, Santulli RJ, Brass LF, Andrade-Gordon P (1998) Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues. J Histochem Cytochem 46:157–164

    PubMed  Google Scholar 

  9. Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, Hoogeveen R, Folsom AR, Heiss G (2003) Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 52:1799–1805

    Article  CAS  PubMed  Google Scholar 

  10. Ebrahimian TG, Heymes C, You D, Blanc-Brude O, Mees B, Waeckel L, Duriez M, Vilar J, Brandes RP, Levy BI, Shah AM, Silvestre J-S (2006) NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes. Am J Pathol 169:719–728

    Article  CAS  PubMed  Google Scholar 

  11. Gao X, Belmadani S, Picchi A, Xu X, Potter BJ, Tewari-Singh N, Capobianco S, Chilian WM, Zhang C (2007) Tumor necrosis factor-alpha induces endothelial dysfunction in Lepr(db) mice. Circulation 115:245–254

    Article  CAS  PubMed  Google Scholar 

  12. Gao X, Zhang H, Schmidt AM, Zhang C (2008) AGE/RAGE produces endothelial dysfunction in coronary arterioles in Type 2 diabetic mice. Am J Physiol Heart Circ Physiol 295:H491–H498

    Article  CAS  PubMed  Google Scholar 

  13. Greenberg AS, McDaniel ML (2002) Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur J Clin Invest 32:24–34

    Article  CAS  PubMed  Google Scholar 

  14. Hamilton JR, Frauman AG, Cocks TM (2001) Increased expression of protease-activated receptor-2 (PAR2) and PAR4 in human coronary artery by inflammatory stimuli unveils endothelium-dependent relaxations to PAR2 and PAR4 agonists. Circ Res 89:92–98

    Article  CAS  PubMed  Google Scholar 

  15. Hirano K (2007) The roles of proteinase-activated receptors in the vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 27:27–36

    Article  CAS  PubMed  Google Scholar 

  16. Hwa JJ, Ghibaudi L, Williams P, Chintala M, Zhang R, Chatterjee M, Sybertz E (1996) Evidence for the presence of a proteinase-activated receptor distinct from the thrombin receptor in vascular endothelial cells. Circ Res 78:581–588

    CAS  PubMed  Google Scholar 

  17. Ihm SH, Chang K, Kim HY, Baek SH, Youn HJ (2010) Peroxisome proliferator-activated receptor-γ activation attenuates cardiac fibrosis in type 2 diabetic rats: the effect of rosiglitazone on myocardial expression of receptor for advanced glycation end products and of connective tissue growth factor. Basic Res Cardiol 105:399–407

    Article  CAS  PubMed  Google Scholar 

  18. Jiang R, Zatta A, Kin H, Wang N, Reeves JG, Mykytenko J, Deneve J, Zhao ZQ, Guyton RA, Vinten-Johansen J (2007) PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in in vivo rat hearts. Am J Physiol Heart Circ Physiol 293:H2845–H2852

    Article  CAS  PubMed  Google Scholar 

  19. Kawabata A, Nakaya Y, Kuroda R, Wakisaka M, Masuko T, Nishikawa H, Kawai K (2003) Involvement of EDHF in the hypotension and increased gastric mucosal blood flow caused by PAR-2 activation in rats. Br J Pharmacol 140:247–254

    Article  CAS  PubMed  Google Scholar 

  20. Kim M-S, Jo H, Um J-Y, Yi J-M, Kim D-K, Choi S-C, Kim T-H, Nah Y-H, Kim H-M, Lee Y-M (2002) Agonists of proteinase-activated receptor 2 induce TNF-alpha secretion from astrocytoma cells. Cell Biochem Funct 20:339–345

    Article  CAS  PubMed  Google Scholar 

  21. Kleinbongard P, Heusch G, Schulz R (2010) TNFα in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther 127:295–314

    Article  CAS  PubMed  Google Scholar 

  22. Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, Thompson PJ (2001) Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. J Allergy Clin Immunol 108:797–803

    Article  CAS  PubMed  Google Scholar 

  23. Lan RS, Stewart GA, Goldie RG, Henry PJ (2004) Altered expression and in vivo lung function of protease-activated receptors during influenza a virus infection in mice. Am J Physiol Lung Cell Mol Physiol 286:L388–L398

    Article  CAS  PubMed  Google Scholar 

  24. Leger AJ, Covic L, Kuliopulos A (2006) Protease-activated receptors in cardiovascular diseases. Circulation 114:1070–1077

    Article  CAS  PubMed  Google Scholar 

  25. Li S, Zhong S, Zeng K, Luo Y, Fea Zhang (2010) Blockade of NF-κB by pyrrolidine dithiocarbamate attenuates myocardial inflammatory response and ventricular dysfunction following coronary microembolization induced by homologous microthrombi in rats. Basic Res Cardiol 105:139–150

    Article  CAS  PubMed  Google Scholar 

  26. Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R (2001) Proteinase-activated receptors. Pharmacol Rev 53:245–282

    CAS  PubMed  Google Scholar 

  27. McGuire JJ (2004) Proteinase-activated receptor 2 (PAR2): a challenging new target for treatment of vascular diseases. Curr Pharm Des 10:2769–2778

    Article  CAS  PubMed  Google Scholar 

  28. McIntosh KA, Plevin R, Ferrell WR, Lockhart JC (2007) The therapeutic potential of proteinase-activated receptors in arthritis. Curr Opin Pharmacol 7:334–338

    Article  CAS  PubMed  Google Scholar 

  29. Nystedt S, Ramakrishnan V, Sundelin J (1996) The proteinase-activated receptor 2 is induced by inflammatory mediators in human endothelial cells. Comparison with the thrombin receptor. J Biol Chem 271:14910–14915

    Article  CAS  PubMed  Google Scholar 

  30. Ossovskaya VS, Bunnett NW (2004) Protease-activated receptors: contribution to physiology and disease. Physiol Rev 84:579–621

    Article  CAS  PubMed  Google Scholar 

  31. Park Y, Capobianco S, Gao X, Falck JR, Dellsperger KC, Zhang C (2008) Role of EDHF in type 2 diabetes-induced endothelial dysfunction. Am J Physiol Heart Circ Physiol 295:H1982–H1988

    Article  CAS  PubMed  Google Scholar 

  32. Picchi A, Gao X, Belmadani S, Potter BJ, Focardi M, Chilian WM, Zhang C (2006) Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ Res 99:69–77

    Article  CAS  PubMed  Google Scholar 

  33. Ritchie E, Saka M, MacKenzie C, Drummond R, Wheeler-Jones C, Kanke T, Plevin R (2007) Cytokine upregulation of proteinase-activated-receptors 2 and 4 expression mediated by p38 MAP kinase and inhibitory kappa B kinase β in human endothelial cells. Br J Pharmacol 150:1044–1054

    Article  CAS  PubMed  Google Scholar 

  34. Robin J, Kharbanda R, McLean P, Campbell R, Vallance P (2003) Protease-activated receptor 2-mediated vasodilatation in humans in vivo: role of nitric oxide and prostanoids. Circulation 107:954–959

    Article  CAS  PubMed  Google Scholar 

  35. Roman-Campos D, Duarte HLL, Sales PA, Natali AJ, Cea Ropert (2009) Changes in cellular contractility and cytokines profile during Trypanosoma cruzi infection in mice. Basic Res Cardiol 104:238–246

    Article  CAS  PubMed  Google Scholar 

  36. Roviezzo F, Bucci M, Brancaleone V, Di Lorenzo A, Geppetti P, Farneti S, Parente L, Lungarella G, Fiorucci S, Cirino G (2005) Proteinase-activated receptor-2 mediates arterial vasodilation in diabetes. Arterioscler Thromb Vasc Biol 25:2349–2354

    Article  CAS  PubMed  Google Scholar 

  37. Sobey CG, Moffatt JD, Cocks TM, Kontos HA (1999) Evidence for selective effects of chronic hypertension on cerebral artery vasodilatation to protease-activated receptor-2 activation. Stroke 30:1933–1941

    CAS  PubMed  Google Scholar 

  38. Trottier G, Hollenberg M, Wang X, Gui Y, Loutzenhiser K, Loutzenhiser R (2002) PAR-2 elicits afferent arteriolar vasodilation by NO-dependent and NO-independent actions. Am J Physiol Renal Physiol 282:F891–F897

    CAS  PubMed  Google Scholar 

  39. Wang J, Zheng H, Hollenberg MD, Wijesuriya SJ, Ou X, Hauer-Jensen M (2003) Up-regulation and activation of proteinase-activated receptor 2 in early and delayed radiation injury in the rat intestine: influence of biological activators of proteinase-activated receptor 2. Radiat Res 160:524–535

    Article  CAS  PubMed  Google Scholar 

  40. Yang J, Park Y, Zhang H, Xu X, Laine GA, Dellsperger KC, Zhang C (2009) Feed-forward signaling of TNF-alpha and NF-kappaB via IKK-beta pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice. Am J Physiol Heart Circ Physiol 296:H1850–H1858

    Article  CAS  PubMed  Google Scholar 

  41. Zhang C (2008) The role of inflammatory cytokines in endothelial dysfunction. Basic Res Cardiol 103:398–406

    Article  CAS  PubMed  Google Scholar 

  42. Zhang C, Hein TW, Wang W, Kuo L (2003) Divergent roles of angiotensin II AT1 and AT2 receptors in modulating coronary microvascular function. Circ Res 92:322–329

    Article  CAS  PubMed  Google Scholar 

  43. Zhang C, Wu C, Xu X, Potter BJ, Gao X (2010) Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury. Basic Res Cardiol 105:453–464

    Article  CAS  PubMed  Google Scholar 

  44. Zhang C, Xu X, Potter BJ, Wang W, Kuo L, Michael L, Bagby GJ, Chilian WM (2006) TNF-alpha contributes to endothelial dysfunction in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol 26:475–480

    Article  CAS  PubMed  Google Scholar 

  45. Zhang H, Zhang J, Ungvari Z, Zhang C (2009) Resveratrol improves endothelial function: role of TNF{alpha} and vascular oxidative stress. Arterioscler Thromb Vasc Biol 29:1164–1171

    Article  CAS  PubMed  Google Scholar 

  46. Zhong B, Wang DH (2009) Protease-activated receptor 2-mediated protection of myocardial ischemia-reperfusion injury: role of transient receptor potential vanilloid receptors. Am J Physiol Regul Integr Comp Physiol 297:R1681–R1690

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from American Heart Association Scientist Development Grant (110350047A), Pfizer Atorvastatin Research Award (2004-37) and NIH grants (RO1-HL077566 and RO1-HL085119) to Dr. Cuihua Zhang.

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Internal Medicine, Medical Pharmacology and Physiology and Nutrition and Exercise Physiology, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO, 65211, USA

    Yoonjung Park, Jiyeon Yang, Hanrui Zhang, Xiaonai Chen & Cuihua Zhang

Authors
  1. Yoonjung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiyeon Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hanrui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaonai Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cuihua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cuihua Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, Y., Yang, J., Zhang, H. et al. Effect of PAR2 in regulating TNF-α and NAD(P)H oxidase in coronary arterioles in type 2 diabetic mice. Basic Res Cardiol 106, 111–123 (2011). https://doi.org/10.1007/s00395-010-0129-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-010-0129-9

Keywords

Search

Navigation