© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts
aLaboratory of Experimental Cardiology, Department of Clinical Sciences and Bioimaging, "G. d'Annunzio" University of Chieti, Ospedale S. Camillo de Lellis, Via Forlanini, 50, 66100 Chieti, Italy
bDepartment of Biomorphology, Biology Section, "G. d'Annunzio" University of Chieti, Chieti, Italy
* Corresponding author. Tel.: +39-0871-41512; fax: +39-0871-402817 rdecater{at}ifc.cnr.it
Objective: We tested the hypothesis of beneficial effects of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitor simvastatin in a model of ischemia–reperfusion, and investigated potential mechanisms. Methods: Isolated working rat hearts were subjected to 15 min global ischemia and 22–180 min reperfusion in the presence or absence of simvastatin (10–100 µM). We evaluated creatinephosphokinase and nitrite levels in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcribed polymerase chain reaction and Western blotting) in the presence or absence of the transcriptional inhibitor actinomycin-D. Results: Simvastatin (25 µM) significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. Protection became less evident at 50 µM and reverted to increased damage at 100 µM. At 25 µM, simvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, probably due to a post-transcriptional regulation since unaltered by animal pretreatment with actinomycin D. Simvastatin also significantly decreased iNOS mRNA and protein, as well as nitrite production after ischemia–reperfusion. The addition of the NOS inhibitor N
-nitro-L-arginine methylester (L-NAME, 30 µM) to 25 µM simvastatin-treated hearts significantly reduced cardioprotection against ischemia–reperfusion. Conclusions: In this model, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant simvastatin concentration reduces ischemia–reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by cholesterol-independent, NO-dependent mechanisms.
KEYWORDS Endothelial function; Nitric oxide; Ischemia; Myocytes; Reperfusion; Statins
1 Present address: Department of Internal Medicine, University of Genoa, Genoa, Italy.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Golomb, A. Nyska, and H. Schwalb Occult Cardiotoxicity--Toxic Effects on Cardiac Ischemic Tolerance Toxicol Pathol, August 1, 2009; 37(5): 572 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Gao, W. Wang, and I. H. Zucker Simvastatin Inhibits Central Sympathetic Outflow in Heart Failure by a Nitric-Oxide Synthase Mechanism J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 278 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Kocsis, J. Pipis, V. Fekete, A. Kovacs-Simon, L. Odendaal, E. Molnar, Z. Giricz, T. Janaky, J. van Rooyen, T. Csont, et al. Lovastatin interferes with the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2406 - H2409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Sun and D. D. Ku Rosuvastatin provides pleiotropic protection against pulmonary hypertension, right ventricular hypertrophy, and coronary endothelial dysfunction in rats Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H801 - H809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ferdinandy, R. Schulz, and G. F. Baxter Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning Pharmacol. Rev., December 1, 2007; 59(4): 418 - 458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Merla, Y. Ye, Y. Lin, S. Manickavasagam, M.-H. Huang, R. J. Perez-Polo, B. F. Uretsky, and Y. Birnbaum The central role of adenosine in statin-induced ERK1/2, Akt, and eNOS phosphorylation Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1918 - H1928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Taylor, M. E. Olsen, and J. W. Starnes Improved postischemic function following acute exercise is not mediated by nitric oxide synthase in the rat heart Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H601 - H607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Patti, M. Chello, V. Pasceri, D. Colonna, A. Nusca, M. Miglionico, A. D'Ambrosio, E. Covino, and G. Di Sciascio Protection From Procedural Myocardial Injury by Atorvastatin Is Associated With Lower Levels of Adhesion Molecules After Percutaneous Coronary Intervention: Results From the ARMYDA-CAMs (Atorvastatin for Reduction of MYocardial Damage during Angioplasty-Cell Adhesion Molecules) Substudy J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1560 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. P. van de Visse, M. van der Heijden, J. Verheij, G. P. van Nieuw Amerongen, V. W. M. van Hinsbergh, A. R. J. Girbes, and A. B. J. Groeneveld Effect of prior statin therapy on capillary permeability in the lungs after cardiac or vascular surgery. Eur. Respir. J., May 1, 2006; 27(5): 1026 - 1032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A D Gavin and A D Struthers Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure Heart, June 1, 2005; 91(6): 749 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Di Napoli, A. A. Taccardi, A. Grilli, M. A. De Lutiis, A. Barsotti, M. Felaco, and R. De Caterina Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts Cardiovasc Res, June 1, 2005; 66(3): 462 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Landmesser, F. Bahlmann, M. Mueller, S. Spiekermann, N. Kirchhoff, S. Schulz, C. Manes, D. Fischer, K. de Groot, D. Fliser, et al. Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans Circulation, May 10, 2005; 111(18): 2356 - 2363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Mensah, M. M. Mocanu, and D. M. Yellon Failure to protect the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment is recaptured by acute atorvastatin treatment: A potential role for phosphatase and tensin homolog deleted on chromosome ten? J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1287 - 1291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schulz Pleiotropic effects of statins: Acutely good, but chronically bad? J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1292 - 1294. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Madonna, P. Di Napoli, M. Massaro, A. Grilli, M. Felaco, A. De Caterina, D. Tang, R. De Caterina, and Y.-J. Geng Simvastatin Attenuates Expression of Cytokine-inducible Nitric-oxide Synthase in Embryonic Cardiac Myoblasts J. Biol. Chem., April 8, 2005; 280(14): 13503 - 13511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Wainwright Statins-is there no end to their usefulness? Cardiovasc Res, February 1, 2005; 65(2): 296 - 298. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Di Nardo Di Maio, Z. Lohinai, C. D'Arcangelo, P. E. De Fazio, L. Speranza, M.A. De Lutiis, A. Patruno, A. Grilli, and M. Felaco Nitric Oxide Synthase in Healthy and Inflamed Human Dental Pulp Journal of Dental Research, April 1, 2004; 83(4): 312 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Eefting, B. Rensing, J. Wigman, W. J. Pannekoek, W. M. Liu, M. J. Cramer, D. J Lips, and P. A Doevendans Role of apoptosis in reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 414 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Varela and J. L. Garvin Acute and Chronic Regulation of Thick Ascending Limb Endothelial Nitric Oxide Synthase by Statins J. Am. Soc. Nephrol., February 1, 2004; 15(2): 269 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kumar, V. Menon, W. R. Ford, A. S. Clanachan, and B. I. Jugdutt Effect of Angiotensin II lype 2 Receptor Blockade on Activation of Mitogen-Activated Protein Kinases after Ischemia-Reperfusion in Isolated Working Rat Hearts Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2003; 8(4): 285 - 296. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Nakamura, S. Al-Ruzzeh, A. H. Chester, C. Ilsley, M. H. Yacoub, and M. Amrani Differential in vitro response of the human radial artery versus left internal thoracic artery to cerivastatin: implications to bypass grafting Ann. Thorac. Surg., December 1, 2003; 76(6): 2023 - 2028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Tiefenbacher, J. Kapitza, V. Dietz, C.-H. Lee, and F. Niroomand Reduction of myocardial infarct size by fluvastatin Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H59 - H64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wolfrum, K. S. Jensen, and J. K. Liao Endothelium-Dependent Effects of Statins Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 729 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Grilli, M. A. De Lutiis, A. Patruno, L. Speranza, F. Gizzi, A. A. Taccardi, P. Di Napoli, R. De Caterina, P. Conti, and M. Felaco Inducible Nitric Oxide Synthase and Heme Oxygenase-1 in Rat Heart: Direct Effect of Chronic Exposure to Hypoxia Ann. Clin. Lab. Sci., April 1, 2003; 33(2): 208 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Schafer, S. Walther, M. Schafer, L. Dieterich, S. Kasseckert, Y. Abdallah, and H.M. Piper Inhibition of contractile activation reduces reoxygenation-induced endothelial gap formation Cardiovasc Res, April 1, 2003; 58(1): 149 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Bell and D. M. Yellon Atorvastatin, administered at the onset of reperfusion, and independent oflipid lowering, protects the myocardiumby up-regulating a pro-survival pathway J. Am. Coll. Cardiol., February 5, 2003; 41(3): 508 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Di Napoli, A.A. Taccardi, M. Oliver, and R. De Caterina Statins and stroke: evidence for cholesterol-independent effects Eur. Heart J., December 2, 2002; 23(24): 1908 - 1921. [PDF]
|
|
|
|
|
|
A. C. Sposito and M. J. Chapman Statin Therapy in Acute Coronary Syndromes: Mechanistic Insight Into Clinical Benefit Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1524 - 1534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nakamura, S. Al-Ruzzeh, A. H. Chester, I. Schmidt, M. Barbir, M. H. Yacoub, and M. Amrani Effects of cerivastatin on vascular function of human radial and left internal thoracic arteries Ann. Thorac. Surg., June 1, 2002; 73(6): 1860 - 1865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu, D. Kumar, J. R. B. Dyck, W. R. Ford, A. S. Clanachan, G. D. Lopaschuk, and B. I. Jugdutt AT1 and AT2 receptor expression and blockade after acute ischemia-reperfusion in isolated working rat hearts Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1206 - H1215. [Abstract] [Full Text] [PDF]
|
|