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Right arrow Transplantation - heart

J Thorac Cardiovasc Surg 2005;129:1160-1167
© 2005 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Inhibition of heart transplant injury and graft coronary artery disease after prolonged organ ischemia by selective protein kinase C regulators

Masashi Tanaka, MDa,*, Feny Gunawana, Raya D. Terrya, Koichi Inagaki, MD, PhDb, Anthony D. Caffarelli, MDa, Grant Hoyta, Philip S. Tsao, PhDc, Daria Mochly-Rosen, PhDb, Robert C. Robbins, MDa

a Department of Cardiothoracic Surgery, Stanford University Medical Center, Stanford, Calif
b Department of Molecular Pharmacology, Stanford University Medical Center, Stanford, Calif
c Department of Cardiovascular Medicine, Stanford University Medical Center, Stanford, Calif

Received for publication June 17, 2004; revisions received September 8, 2004; accepted for publication September 20, 2004.

* Address for reprints: Masashi Tanaka, MD, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, CA 94305 (E-mail: masahi{at}omiya.jichi.ac.jp).

OBJECTIVE: Transplanted hearts subjected to prolonged ischemia develop ischemia-reperfusion injury and graft coronary artery disease. To determine the effect of {delta}-protein kinase C and {epsilon}-protein kinase C on ischemia-reperfusion injury and the resulting graft coronary artery disease induced by prolonged ischemia, we used a {delta}-protein kinase C-selective inhibitor peptide and an {epsilon}-protein kinase C-selective activator peptide after 30 or 120 minutes of ischemia.

METHODS: Hearts of piebald viral glaxo (PVG) rats were heterotopically transplanted into allogeneic August Copenhagen Irish (ACI) rats. After cardioplegic arrest of the donor heart, {epsilon}-protein kinase C activator was injected antegrade into the coronary arteries. Hearts were procured and bathed in {epsilon}-protein kinase C activator, and before reperfusion, {delta}-protein kinase C inhibitor was injected into the recipient inferior vena cava. Controls were treated with saline. To analyze ischemia-reperfusion injury, grafts were procured at 4 hours after transplantation and analyzed for superoxide generation; myeloperoxidase activity; tumor necrosis factor {alpha}, interleukin 1ß, and monocyte/macrophage chemoattractant protein 1 production; and cardiomyocyte apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and caspase 2, 3, 8, and 9 activity. To analyze graft coronary artery disease, another set of animals underwent equal ischemic times and treatment strategies and then after 90 days were analyzed for graft coronary artery disease indexes.

RESULTS: All measures of ischemia-reperfusion injury and graft coronary artery disease after 120 minutes of ischemia in the saline-treated group were significantly increased relative to those observed after 30 minutes of ischemia. It is important to note that all ischemia-reperfusion injury parameters and graft coronary artery disease indexes decreased significantly in the protein kinase C regulator-treated group in comparison to saline-treated controls; additionally, these values were equivalent to those in saline-treated controls with 30 minutes of ischemia.

CONCLUSIONS: Combined treatment with {epsilon}-protein kinase C activator and {delta}-protein kinase C inhibitor reduces ischemia-reperfusion injury and decreases the resulting graft coronary artery disease induced by prolonged ischemia.




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