EXPERIMENTAL STUDY
Atorvastatin, administered at the onset of reperfusion, and independent oflipid lowering, protects the myocardiumby up-regulating a pro-survival pathway
Robert M. Bell, MBBS, BSc, PhD* and
Derek M. Yellon, PhD, DSc, Hon FRCP, FACC*,*
* The Hatter Institute for Cardiovascular Studies, Academic and Clinical Cardiology, Division of Medicine, University College Hospitals and Medical School, University College, London, London, United Kingdom
Manuscript received August 9, 2002;
revised manuscript received September 19, 2002,
accepted October 31, 2002.
* Reprint requests and correspondence: Dr. Derek M. Yellon, The Hatter Institute for Cardiovascular Studies, Academic and Clinical Cardiology, Division of Medicine, University College Hospitals and Medical School, University College, London, Grafton Way, London, UK WC1E 6DB.
hatter-institute{at}ucl.ac.uk
OBJECTIVES: The purpose of this study was to determine whether atorvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-co-enzyme A (CoA) reductase inhibitor, limits myocardial necrosis when administered as an adjunct to reperfusion.
BACKGROUND: Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol. However, it is proposed that statins have cardiovascular effects beyond their ability to lower cholesterol, possibly via recruitment of phosphatidyl inositol 3-kinase (PI3K) and the serine/threonine kinase, Akt. This signaling pathway has recently been linked to growth factor–mediated reperfusion salvage.
METHODS: Isolated perfused mouse hearts were subjected to 35 min of global ischemia and reperfused for 30 min in the presence of incremental concentrations of atorvastatin. Infarct size was determined by triphenyltetrazolium chloride staining, and the activity of the PI3K signaling cascade was determined by Western blot analysis.
RESULTS: We found that there was a profound dose-dependent reduction of infarct size with atorvastatin in the range of 25 to 100 µmol/l (optimal protection was seen at 50 µmol/l with infarct size of 16 ± 2% vs. control, 33 ± 2%, p < 0.01). Moreover, this protection was sensitive to inhibition with the PI3 kinase inhibitor, wortmannin, and was absent in endothelial nitric oxide synthase (eNOS) knockout mice. Western blot analysis revealed that atorvastatin resulted in rapid activation of the PI3K/Akt signaling cascade (within 5 min) and that both Akt and eNOS phosphorylation were significantly increased by 4.1-fold and 2.9-fold, respectively (p < 0.01). Moreover, phosphorylation of the PI3K substrates was abrogated by the administration of wortmannin.
CONCLUSIONS: Atorvastatin attenuates lethal reperfusion-induced injury in a manner that is reliant on PI3K and Akt activity and the presence and activity of eNOS.
|
Abbreviations and Acronyms
| | AU | | arbitrary units | | DMSO | | dimethyl sulfoxide | | eNOS | | endothelial nitric oxide synthase | | HMG-CoA | | 3-hydroxy-3-methylglutaryl-co-enzyme A | | KO | | knockout | | PI3K | | phosphatidyl inositol 3-kinase | | TTC | | triphenyl tetrazolium chloride |
|
This article has been cited by other articles:
|
|
|
|
 
G. Di Sciascio, G. Patti, V. Pasceri, A. Gaspardone, G. Colonna, and A. Montinaro
Efficacy of Atorvastatin Reload in Patients on Chronic Statin Therapy Undergoing Percutaneous Coronary Intervention: Results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) Randomized Trial
J. Am. Coll. Cardiol.,
July 1, 2009;
(2009)
j.jacc.2009.05.028v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Ishii, T. Amano, T. Matsubara, and T. Murohara
Pharmacological Intervention for Prevention of Left Ventricular Remodeling and Improving Prognosis in Myocardial Infarction
Circulation,
December 16, 2008;
118(25):
2710 - 2718.
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ye, Y. Lin, S. Manickavasagam, J. R. Perez-Polo, B. C. Tieu, and Y. Birnbaum
Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice
Am J Physiol Heart Circ Physiol,
December 1, 2008;
295(6):
H2436 - H2446.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ye, J. D. Martinez, R. J. Perez-Polo, Y. Lin, B. F. Uretsky, and Y. Birnbaum
The role of eNOS, iNOS, and NF-{kappa}B in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin
Am J Physiol Heart Circ Physiol,
July 1, 2008;
295(1):
H343 - H351.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-J. Yang, H.-Y. Qian, J. Huang, Y.-J. Geng, R.-L. Gao, K.-F. Dou, G.-S. Yang, J.-J. Li, R. Shen, Z.-X. He, et al.
Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts
Eur. Heart J.,
June 2, 2008;
29(12):
1578 - 1590.
[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]
|
|
|
|
|
|
|
Y. Birnbaum, Y. Lin, Y. Ye, R. Merla, J. R. Perez-Polo, and B. F. Uretsky
Pretreatment With High-Dose Statin, But Not Low-Dose Statin, Ezetimibe, or the Combination of Low-Dose Statin and Ezetimibe, Limits Infarct Size in the Rat
Journal of Cardiovascular Pharmacology and Therapeutics,
March 1, 2008;
13(1):
72 - 79.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. J. Davidson and D. S. Baim
Percutaneous Aortic Valve Interventions
Card. Surg. Adult,
January 1, 2008;
3(2008):
963 - 971.
[Full Text]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
L. Zhang, Z. G. Zhang, X. S. Liu, A. Hozeska-Solgot, and M. Chopp
The PI3K/Akt Pathway Mediates the Neuroprotective Effect of Atorvastatin in Extending Thrombolytic Therapy After Embolic Stroke in the Rat
Arterioscler. Thromb. Vasc. Biol.,
November 1, 2007;
27(11):
2470 - 2475.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Yellon and D. J. Hausenloy
Myocardial Reperfusion Injury
N. Engl. J. Med.,
September 13, 2007;
357(11):
1121 - 1135.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Yin, J. Zhu, Z. Wang, H. Huang, J. Qian, Z. Li, and H. Jing
Simvastatin attenuates cardiac isograft ischemia-reperfusion injury by down-regulating CC chemokine receptor-2 expression
J. Thorac. Cardiovasc. Surg.,
September 1, 2007;
134(3):
780 - 788.
[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]
|
|
|
|
|
|
|
J. Afilalo, A. A Majdan, and M. J Eisenberg
Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials
Heart,
August 1, 2007;
93(8):
914 - 921.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ye, Y. Lin, R. Perez-Polo, M.-H. Huang, M. G. Hughes, D. J. McAdoo, S. Manickavasagam, B. F. Uretsky, and Y. Birnbaum
Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination
Am J Physiol Heart Circ Physiol,
July 1, 2007;
293(1):
H813 - H818.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Bulhak, J. Roy, U. Hedin, P.-O. Sjoquist, and J. Pernow
Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation
Am J Physiol Heart Circ Physiol,
June 1, 2007;
292(6):
H3158 - H3163.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Davidson and M. R. Duchen
Endothelial Mitochondria: Contributing to Vascular Function and Disease
Circ. Res.,
April 27, 2007;
100(8):
1128 - 1141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Patti, V. Pasceri, G. Colonna, M. Miglionico, D. Fischetti, G. Sardella, A. Montinaro, and G. Di Sciascio
Atorvastatin Pretreatment Improves Outcomes in Patients With Acute Coronary Syndromes Undergoing Early Percutaneous Coronary Intervention: Results of the ARMYDA-ACS Randomized Trial
J. Am. Coll. Cardiol.,
March 27, 2007;
49(12):
1272 - 1278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ye, Y. Lin, S. Atar, M.-H. Huang, J. R. Perez-Polo, B. F. Uretsky, and Y. Birnbaum
Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions
Am J Physiol Heart Circ Physiol,
September 1, 2006;
291(3):
H1158 - H1169.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Wang, D. A. Neff, J. G. Krolikowski, D. Weihrauch, M. Bienengraeber, D. C. Warltier, J. R. Kersten, and P. S. Pagel
The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits.
Anesth. Analg.,
May 1, 2006;
102(5):
1355 - 1360.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Abdallah, A. Gkatzoflia, D. Gligorievski, S. Kasseckert, G. Euler, K.-D. Schluter, M. Schafer, H.-M. Piper, and C. Schafer
Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture by a survival pathway targeting SR Ca2+ storage
Cardiovasc Res,
May 1, 2006;
70(2):
346 - 353.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Iwakura, H. Ito, S. Kawano, A. Okamura, T. Kurotobi, M. Date, K. Inoue, and K. Fujii
Chronic pre-treatment of statins is associated with the reduction of the no-reflow phenomenon in the patients with reperfused acute myocardial infarction
Eur. Heart J.,
March 1, 2006;
27(5):
534 - 539.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. V. Solenkova, V. Solodushko, M. V. Cohen, and J. M. Downey
Endogenous adenosine protects preconditioned heart during early minutes of reperfusion by activating Akt
Am J Physiol Heart Circ Physiol,
January 1, 2006;
290(1):
H441 - H449.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Abdallah and C. Schafer
Insulin: An overall cardiovascular protector?
Cardiovasc Res,
January 1, 2006;
69(1):
4 - 6.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Herrmann
Peri-procedural myocardial injury: 2005 update
Eur. Heart J.,
December 1, 2005;
26(23):
2493 - 2519.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. K. Ray and C. P. Cannon
The Potential Relevance of the Multiple Lipid-Independent (Pleiotropic) Effects of Statins in the Management of Acute Coronary Syndromes
J. Am. Coll. Cardiol.,
October 18, 2005;
46(8):
1425 - 1433.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Weihrauch, J. G. Krolikowski, M. Bienengraeber, J. R. Kersten, D. C. Warltier, and P. S. Pagel
Morphine Enhances Isoflurane-Induced Postconditioning Against Myocardial Infarction: The Role of Phosphatidylinositol-3-Kinase and Opioid Receptors in Rabbits
Anesth. Analg.,
October 1, 2005;
101(4):
942 - 949.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Tsang, D. J. Hausenloy, and D. M. Yellon
Myocardial postconditioning: reperfusion injury revisited
Am J Physiol Heart Circ Physiol,
July 1, 2005;
289(1):
H2 - H7.
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. S. Ali and K. J. Buth
Preoperative statin use and in-hospital outcomes following heart surgery in patients with unstable angina
Eur. J. Cardiothorac. Surg.,
June 1, 2005;
27(6):
1051 - 1056.
[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]
|
|
|
|
|
|
|
S. Sanada, H. Asanuma, T. Minamino, K. Node, S. Takashima, H. Okuda, Y. Shinozaki, A. Ogai, M. Fujita, A. Hirata, et al.
Optimal Windows of Statin Use for Immediate Infarct Limitation: 5'-Nucleotidase as Another Downstream Molecule of Phosphatidylinositol 3-Kinase
Circulation,
October 12, 2004;
110(15):
2143 - 2149.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Campbell, W. E. Allen, C. Sawyer, B. Vanhaesebroeck, and E. R. Trimble
Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways
Circ. Res.,
August 20, 2004;
95(4):
380 - 388.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. Harris, M. A. Blackstone, S. G. Sood, C. Li, J. M. Goolsby, V. J. Venema, B. E. Kemp, and R. C. Venema
Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors
Am J Physiol Heart Circ Physiol,
August 1, 2004;
287(2):
H560 - H566.
[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]
|
|
|
|
|
|
|
D. J Hausenloy and D. M Yellon
New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway
Cardiovasc Res,
February 15, 2004;
61(3):
448 - 460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Woodcock
Unc-II and Unc-III Are Cardioprotective against Ischemia Reperfusion Injury: An Essential Endogenous Cardioprotective Role for CRFR2 in the Murine Heart
Endocrinology,
January 1, 2004;
145(1):
21 - 23.
[Full Text]
[PDF]
|
|
|
|
