Skip to main content

Advertisement

SpringerLink
Log in

Cardioprotection mediated by rosiglitazone, a peroxisome proliferatoractivated receptor gamma ligand, in relation to nitric oxide

  • ORIGINAL CONTRIBUTION
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Activation of peroxisome proliferator-activated receptor (PPAR) gamma protects from myocardial ischemia/reperfusion injury. The aim of the study was to investigate whether the cardioprotective effect of PPARgamma is related to nitric oxide (NO).

Methods

Wild type (WT) and endothelial NO synthase (eNOS) knockout (KO) mice received 3 mg/kg of the PPARgamma agonist rosiglitazone or vehicle (n = 6–9 in each group) i. p. 45 min before anesthesia. The hearts were isolated, perfused in a Langendorff mode and subjected to global ischemia and 30 min reperfusion. The hearts of another two groups ofWT mice received the NOS inhibitor L-NNA (100 ìmol/l) or vehicle in addition to pre-treatment with vehicle or rosiglitazone.

Results

In the WT heart, rosiglitazone increased the recovery of left ventricular function and coronary flow following ischemia in comparison with the vehicle group.L-NNA did not affect recovery per se but significantly blunted the improvement in the recovery of left ventricular function induced by rosiglitazone. In the KO group rosiglitazone suppressed the recovery of myocardial function following ischemia. Expression of eNOS was not affected, but phosphorylated eNOS was significantly increased by rosiglitazone in the WT hearts (P < 0.05).

Conclusion

These results suggest that the cardioprotective effect of the PPARgamma agonist rosiglitazone is mediated via NO by phosphorylation of eNOS.

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

Similar content being viewed by others

References

  1. Bagi Z, Koller A, Kaley G (2004) PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. Am J Physiol Heart Circ Physiol 286:H742–H748

    Article  PubMed  CAS  Google Scholar 

  2. Bulhak AA, Gourine AV, Gonon AT, Sjoquist PO, Valen G, Pernow J (2005) Oral pre-treatment with rosuvastatin protects porcine myocardium from ischaemia/ reperfusion injury via a mechanism related to nitric oxide but not to serum cholesterol level. Acta Physiol Scand 183:151–159

    Article  PubMed  CAS  Google Scholar 

  3. Bulhak AA, Sjoquist PO, Xu CB, Edvinsson L, Pernow J (2006) Protection against myocardial ischaemia/reperfusion injury by PPAR-alpha activation is related to production of nitric oxide and endothelin-1. Basic Res Cardiol 101:244–252

    Article  PubMed  CAS  Google Scholar 

  4. Calnek DS, Mazzella L, Roser S, Roman J, Hart CM (2003) Peroxisome proliferator- activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 23:52–57

    Article  PubMed  CAS  Google Scholar 

  5. Cho DH, Choi YJ, Jo SA, Jo I (2004) Nitric oxide production and regulation of endothelial nitric-oxide synthase phosphorylation by prolonged treatment with troglitazone: evidence for involvement of peroxisome proliferator-activated receptor (PPAR) gamma-dependent and PPARgamma-independent signaling pathways. J Biol Chem 279:2499–2506

    Article  PubMed  CAS  Google Scholar 

  6. Cotton JM, Kearney MT, Shah AM (2002) Nitric oxide and myocardial function in heart failure: friend or foe? Heart 88:564–566

    Article  PubMed  CAS  Google Scholar 

  7. Csonka C, Szilvassy Z, Fulop F, Pali T, Blasig IE, Tosaki A, Schulz R, Ferdinandy P (1999) Classic preconditioning decreases the harmful accumulation of nitric oxide during ischemia and reperfusion in rat hearts. Circulation 100:2260–2266

    CAS  Google Scholar 

  8. Delerive P, Martin-Nizard F, Chinetti G, Trottein F, Fruchart JC, Najib J, Duriez P, Staels B (1999) Peroxisome proliferator- activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res 85:394–402

    PubMed  CAS  Google Scholar 

  9. Ferdinandy P, Schulz R (2003) Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion injury and preconditioning. Br J Pharmacol 138:532–543

    Article  PubMed  CAS  Google Scholar 

  10. Fleming I, Busse R (2003) Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol 284:R1–R12

    PubMed  CAS  Google Scholar 

  11. Gilde AJ, Van Bilsen M (2003) Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiol Scand 178:425–434

    Article  PubMed  CAS  Google Scholar 

  12. Gonon AT, Erbas D, Broijersen A,Valen G, Pernow J (2004) Nitric oxide mediates protective effect of endothelin receptor antagonism during myocardial ischemia and reperfusion. Am J Physiol Heart Circ Physiol 286:H1767–H1774

    Article  PubMed  CAS  Google Scholar 

  13. Heusch G, Post H, Michel MC, Kelm M, Schulz R (2000) Endogenous nitric oxide and myocardial adaptation to ischemia. Circ Res 87:146–152

    PubMed  CAS  Google Scholar 

  14. Hwang J, Kleinhenz DJ, Lassegue B, Griendling KK, Dikalov S, Hart CM (2005) Peroxisome proliferator-activated receptor-gamma ligands regulate endothelial membrane superoxide production. Am J Physiol Cell Physiol 288:C899–C905

    Article  PubMed  CAS  Google Scholar 

  15. Inoue I, Goto S, Matsunaga T, Nakajima T, Awata T, Hokari S, Komoda T, Katayama S (2001) The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism 50:3–11

    Article  PubMed  CAS  Google Scholar 

  16. Jiang C, Ting AT, Seed B (1998) PPARgamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82–86

    Article  PubMed  CAS  Google Scholar 

  17. Kanno S, Lee PC, Zhang Y, Ho C, Griffith BP, Shears LL, 2nd, Billiar TR (2000) Attenuation of myocardial ischemia/ reperfusion injury by superinduction of inducible nitric oxide synthase. Circulation 101:2742–2748

    PubMed  CAS  Google Scholar 

  18. Khandoudi N, Delerive P, Berrebi-Bertrand I, Buckingham RE, Staels B, Bril A (2002) Rosiglitazone, a peroxisome proliferator-activated receptorgamma, inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/ reperfusion injury. Diabetes 51:1507–1514

    PubMed  CAS  Google Scholar 

  19. Lin MI, Fulton D, Babbitt R, Fleming I, Busse R, Pritchard KA, Jr., Sessa WC (2003) Phosphorylation of threonine 497 in endothelial nitric-oxide synthase coordinates the coupling of L-arginine metabolism to efficient nitric oxide production. J Biol Chem 278:44719–44726

    Article  PubMed  CAS  Google Scholar 

  20. Liu HR,Tao L, Gao E, Lopez BL, Christopher TA, Willette RN, Ohlstein EH, Yue TL, Ma XL (2004) Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion. Cardiovasc Res 62:135–144

    Article  PubMed  CAS  Google Scholar 

  21. Marx N, Walcher D, Ivanova N, Rautzenberg K, Jung A, Friedl R, Hombach V, de Caterina R, Basta G, Wautier MP, Wautiers JL (2004) Thiazolidinediones reduce endothelial expression of receptors for advanced glycation end products. Diabetes 53:2662–2668

    PubMed  CAS  Google Scholar 

  22. Mendez M, LaPointe MC (2003) PPARgamma inhibition of cyclooxygenase- 2, PGE2 synthase, and inducible nitric oxide synthase in cardiac myocytes. Hypertension 42:844–850

    Article  PubMed  CAS  Google Scholar 

  23. Onody A, Zvara A, Hackler L, Jr., Vigh L, Ferdinandy P, Puskas LG (2003) Effect of classic preconditioning on the gene expression pattern of rat hearts: a DNA microarray study. FEBS Lett 536:35–40

    Article  PubMed  CAS  Google Scholar 

  24. Sharp BR, Jones SP, Rimmer DM, Lefer DJ (2002) Differential response to myocardial reperfusion injury in eNOSdeficient mice. Am J Physiol Heart Circ Physiol 282:H2422–H2426

    PubMed  CAS  Google Scholar 

  25. Sidell RJ, Cole MA, Draper NJ, Desrois M, Buckingham RE, Clarke K (2002) Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart. Diabetes 51:1110–1117

    PubMed  CAS  Google Scholar 

  26. Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C (2002) Ligands of the peroxisome proliferatoractivated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. Faseb J 16:1027–1040

    Article  PubMed  CAS  Google Scholar 

  27. Wright DG, Lefer DJ (2005) Statin mediated protection of the ischemic myocardium. Vascul Pharmacol 42:265–270

    Article  PubMed  CAS  Google Scholar 

  28. Xu Y, Lu L, Greyson C, Lee J, Gen M, Kinugawa K, Long CS, Schwartz GG (2003) Deleterious effects of acute treatment with a peroxisome proliferator-activated receptor-gamma activator in myocardial ischemia and reperfusion in pigs. Diabetes 52:1187–1194

    PubMed  CAS  Google Scholar 

  29. Yasmin W, Strynadka KD, Schulz R (1997) Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts. Cardiovasc Res 33:422–432

    Article  PubMed  CAS  Google Scholar 

  30. Young PW, Cawthorne MA, Coyle PJ, Holder JC, Holman GD, Kozka IJ, Kirkham DM, Lister CA, Smith SA (1995) Repeat treatment of obese mice with BRL 49653, a new potent insulin sensitizer, enhances insulin action in white adipocytes. Association with increased insulin binding and cell-surface GLUT4 as measured by photoaffinity labeling. Diabetes 44:1087–1092

    PubMed  CAS  Google Scholar 

  31. Yue Tl TL, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, Lysko PG, Gu JL, Boyce R, Zimmerman DM, Hart TK, Buckingham RE, Ohlstein EH (2001) In vivo myocardial protection from ischemia/ reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 104:2588–2594

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dept. of Cardiology, Karolinska University Hospital, Solna, 17176, Stockholm, Sweden

    A. T. Gonon MD, PhD, A. Bulhak, P.-O. Sjöquist & J. Pernow

  2. Crafoord Laboratory of Experimental Surgery, Karolinska University Hospital, Solna, Stockholm, Sweden

    F. Labruto

Authors
  1. A. T. Gonon MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Bulhak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Labruto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P.-O. Sjöquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Pernow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. T. Gonon MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gonon, A.T., Bulhak, A., Labruto, F. et al. Cardioprotection mediated by rosiglitazone, a peroxisome proliferatoractivated receptor gamma ligand, in relation to nitric oxide. Basic Res Cardiol 102, 80–89 (2007). https://doi.org/10.1007/s00395-006-0613-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-006-0613-4

Key words

Search

Navigation