TY - JOUR
T1 - Inhibition of heart transplant injury and graft coronary artery disease after prolonged organ ischemia by selective protein kinase C regulators
AU - Tanaka, Masashi
AU - Gunawan, Feny
AU - Terry, Raya D.
AU - Inagaki, Koichi
AU - Caffarelli, Anthony D.
AU - Hoyt, Grant
AU - Tsao, Philip S.
AU - Mochly-Rosen, Daria
AU - Robbins, Robert C.
N1 - Funding Information:
Supported by National Institutes of Health grants HL65669 (R.C.R.) and HL52141 (D.M.-R.).D.M.-R. is a founder of KAI Pharmaceuticals, the goal of which is to bring peptide regulators of PKC to the clinic. The research described in this study, however, was performed in collaboration with her laboratory at the university with sole support from the National Institutes of Health to her university activities.
PY - 2005/5
Y1 - 2005/5
N2 - Objective: Transplanted hearts subjected to prolonged ischemia develop ischemia-reperfusion injury and graft coronary artery disease. To determine the effect of δ-protein kinase C and ε-protein kinase C on ischemia-reperfusion injury and the resulting graft coronary artery disease induced by prolonged ischemia, we used a δ-protein kinase C-selective inhibitor peptide and an ε-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, ε-protein kinase C activator was injected antegrade into the coronary arteries. Hearts were procured and bathed in ε-protein kinase C activator, and before reperfusion, δ-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 α, interleukin 1β, 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 ε-protein kinase C activator and δ-protein kinase C inhibitor reduces ischemia-reperfusion injury and decreases the resulting graft coronary artery disease induced by prolonged ischemia.
AB - Objective: Transplanted hearts subjected to prolonged ischemia develop ischemia-reperfusion injury and graft coronary artery disease. To determine the effect of δ-protein kinase C and ε-protein kinase C on ischemia-reperfusion injury and the resulting graft coronary artery disease induced by prolonged ischemia, we used a δ-protein kinase C-selective inhibitor peptide and an ε-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, ε-protein kinase C activator was injected antegrade into the coronary arteries. Hearts were procured and bathed in ε-protein kinase C activator, and before reperfusion, δ-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 α, interleukin 1β, 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 ε-protein kinase C activator and δ-protein kinase C inhibitor reduces ischemia-reperfusion injury and decreases the resulting graft coronary artery disease induced by prolonged ischemia.
UR - http://www.scopus.com/inward/record.url?scp=18244393167&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=18244393167&partnerID=8YFLogxK
U2 - 10.1016/j.jtcvs.2004.09.015
DO - 10.1016/j.jtcvs.2004.09.015
M3 - Article
AN - SCOPUS:18244393167
SN - 0022-5223
VL - 129
SP - 1160
EP - 1167
JO - Journal of Thoracic and Cardiovascular Surgery
JF - Journal of Thoracic and Cardiovascular Surgery
IS - 5
ER -