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

Abstract

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 -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 -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, -protein kinase C activator was injected antegrade into the coronary arteries. Hearts were procured and bathed in -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 1beta, 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 -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.

• Authors: Masashi Tanaka, Feny Gunawan, Raya D Terry, Koichi Inagaki, Anthony D Caffarelli, Grant Hoyt, Philip S Tsao, Daria Mochly-Rosen, Robert C Robbins
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 129 Issue 5 Pg. 1160-7 (May 2005) ISSN: 0022-5223 [Print] United States
• PMID: 15867794 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• His-Asp-Ala-Pro-Ile-Gly-Tyr-Asp
• Oligopeptides
• Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Glu-Ser-Leu
• Superoxides
• Peroxidase
• Prkce protein, rat
• Protein Kinase C
• Protein Kinase C-epsilon
• Caspases

Topics

• Animals
• Apoptosis
• Caspases (analysis, metabolism)
• Coronary Disease (diagnosis, etiology, metabolism, prevention & control)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Drug Therapy, Combination
• Enzyme-Linked Immunosorbent Assay
• Graft Rejection
• Heart Transplantation (adverse effects)
• In Situ Nick-End Labeling
• Inflammation
• Male
• Myocardial Reperfusion Injury (diagnosis, etiology, metabolism, prevention & control)
• Myocardium (chemistry)
• Oligopeptides (therapeutic use)
• Peroxidase (analysis, metabolism)
• Protein Kinase C (antagonists & inhibitors, physiology)
• Protein Kinase C-epsilon
• Rats
• Rats, Inbred Strains
• Severity of Illness Index
• Superoxides (analysis, metabolism)
• Time Factors
• Transplantation, Heterotopic