HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Meena Nathan Ingeborg Friehs Yeong-Hoon Choi Pedro J. del Nido Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nathan, M. Articles by del Nido, P. J. Search for Related Content PubMed PubMed Citation Articles by Nathan, M. Articles by del Nido, P. J. Related Collections Myocardial protection

Ann Thorac Surg 2005;79:1620-1626
© 2005 The Society of Thoracic Surgeons

---

Original articles: Cardiovascular

Cyclosporin A But Not FK-506 Protects Against Dopamine-Induced Apoptosis in the Stunned Heart

^a Department of Cardiac Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts
^b Department of Anesthesiology and Pain Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts

Accepted for publication October 19, 2004.

^_* Address reprint requests to Dr del Nido, Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Ave, Bader 279, Boston, MA 02115 (E-mail: pedro.delnido{at}tch.harvard.edu).

BACKGROUND: Dopamine given at moderate doses for inotropy to postischemic hearts has been shown to augment myocyte apoptosis in association with elevated cytosolic calcium. We hypothesize that dopamine-mediated apoptosis occurs through calcium-induced opening of the mitochondrial permeability transition (mPT) pore. We also hypothesize that cyclosporin A (CSA), a calcineurin inhibitor known to block mPT pore opening, would prevent dopamine-induced apoptosis primarily by inhibiting pore opening (cyclophilin D binding).

METHODS: Isolated perfused rabbit hearts (n = 6/group) were subjected to 30 minutes of 37°C cardioplegic arrest followed by 120 minutes reperfusion (ischemic injury that produces < 3% infarct by triphenyl-tetrazolium chloride [TTC] staining). Four groups were studied: (1) control; (2) dopamine (10 µmol/L) postischemia (dopa); (3) dopamine+CSA (0.2 µmol/L) (CSA+D) group; (4) dopamine+FK-506 (0.2 µmol/L) (FK+D) group. Left ventricular developed pressure and oxygen consumption were measured preischemia and postischemia. Bax, caspase-3 and caspase-9, and poly-ADP-ribose polymerase (PARP) activation were measured by Western blotting. Apoptotic nuclei were quantified by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining.

RESULTS: Dopamine postischemia improved contractile function and heart rate and this was not affected by CSA or FK. However, TUNEL positive nuclei, Bax, caspase-3 and caspase-9 activation, and PARP cleavage were all increased in dopa and FK+D groups, but not in CSA+D.

CONCLUSIONS: Cyclosporin is effective in preventing dopamine-induced apoptosis in the postischemic heart. The mechanism is likely due to inhibition of mPT pore opening since FK-506, a potent calcineurin inhibitor that does not bind to cyclophilin, did not prevent this. Low dose cyclosporin may prove useful to prevent dopamine-induced apoptosis resulting in long-term preservation of cardiac function.

This article has been cited by other articles:

				B. G. Leshnower, S. Kanemoto, M. Matsubara, H. Sakamoto, R. Hinmon, J. H. Gorman III, and R. C. Gorman Cyclosporine Preserves Mitochondrial Morphology After Myocardial Ischemia/Reperfusion Independent of Calcineurin Inhibition Ann. Thorac. Surg., October 1, 2008; 86(4): 1286 - 1292. [Abstract] [Full Text] [PDF]

				N. Oka, L. Wang, W. Mi, and C. A. Caldarone Inhibition of mitochondrial remodeling by cyclosporine A preserves myocardial performance in a neonatal rabbit model of cardioplegic arrest J. Thorac. Cardiovasc. Surg., March 1, 2008; 135(3): 585 - 593. [Abstract] [Full Text] [PDF]

				N. Oka, L. Wang, W. Mi, W. Zhu, O. Honjo, and C. A. Caldarone Cyclosporine A prevents apoptosis-related mitochondrial dysfunction after neonatal cardioplegic arrest J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 123 - 130. [Abstract] [Full Text] [PDF]

				S. M. MacDonnell, H. Kubo, D. M. Harris, X. Chen, R. Berretta, M. F. Barbe, S. Kolwicz, P. O. Reger, A. Eckhart, B. F. Renna, et al. Calcineurin inhibition normalizes beta-adrenergic responsiveness in the spontaneously hypertensive rat Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3122 - H3129. [Abstract] [Full Text] [PDF]

				N. Roy, I. Friehs, D. B. Cowan, D. Zurakowski, F. X. McGowan, and P. J. del Nido Dopamine Induces Postischemic Cardiomyocyte Apoptosis In Vivo: An Effect Ameliorated by Propofol Ann. Thorac. Surg., December 1, 2006; 82(6): 2192 - 2199. [Abstract] [Full Text] [PDF]

				N. Gavini, S. Tungtur, and L. Pulakat Peptidyl-Prolyl cis/trans Isomerase-Independent Functional NifH Mutant of Azotobacter vinelandii. J. Bacteriol., August 1, 2006; 188(16): 6020 - 6025. [Abstract] [Full Text] [PDF]