Prevention of transplant coronary artery disease by prenylation inhibitors
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Prevention of transplant coronary artery disease by prenylation inhibitors. / Stein, William; Schrepfer, Sonja; Itoh, Satoshi; Kimura, Naoyuki; Velotta, Jeffrey; Palmer, Owen; Bartos, Jason; Wang, Xi; Robbins, Robert C; Fischbein, Michael P.
in: J HEART LUNG TRANSPL, Jahrgang 30, Nr. 7, 07.2011, S. 761-769.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Prevention of transplant coronary artery disease by prenylation inhibitors
AU - Stein, William
AU - Schrepfer, Sonja
AU - Itoh, Satoshi
AU - Kimura, Naoyuki
AU - Velotta, Jeffrey
AU - Palmer, Owen
AU - Bartos, Jason
AU - Wang, Xi
AU - Robbins, Robert C
AU - Fischbein, Michael P
N1 - Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
PY - 2011/7
Y1 - 2011/7
N2 - BACKGROUND: In this study we systematically dissect the prenylation pathway to better define the mechanism behind statin inhibition in chronic allograft rejection in heart transplants, or transplant coronary artery disease (TCAD).METHODS: Utilizing a murine heterotopic heart transplant model, animals received daily treatments of either statin or selective isoprenoid blockade inhibitors to block the four major downstream branches of the mevalonate pathway. TCAD was assessed by morphometric analysis at Day 52. Graft-infiltrating cells, cytokine production, smooth muscle cell proliferation and migration and endothelial cell MHC II expression were detected on Day 7.RESULTS: Atorvastatin and two prenylation inhibitors, NE-10790 and manumycin A, significantly reduced TCAD lesions compared with untreated animals. Perillyl alcohol treatment resulted in a trend toward decreased luminal narrowing. Finally, zaragozic acid (cholesterol blockade only) did not alter TCAD severity. Statins and prenylation inhibitors reduced inflammatory cell allograft recruitment, but did not always correlate with TCAD reduction. Cytokine production was decreased in recipient spleens in all treatment groups. Both in vitro and in vivo IFN-γ-stimulated MHC II expression was decreased in a dose-dependent manner in the atorvastatin, perillyl alcohol and NE-10790 groups. In vitro smooth muscle cell proliferation was decreased in all treatment groups. Finally, in vitro smooth muscle cell migration was decreased in the atorvastatin, NE-10790 and manumycin A groups only.CONCLUSIONS: FPT and GGPT-2 (inhibition) are the key enzymes in the HGM-CoA reductase pathway and most influential in TCAD prevention. TCAD reduction is most closely related to smooth muscle cell migration, but not its anti-inflammatory properties.
AB - BACKGROUND: In this study we systematically dissect the prenylation pathway to better define the mechanism behind statin inhibition in chronic allograft rejection in heart transplants, or transplant coronary artery disease (TCAD).METHODS: Utilizing a murine heterotopic heart transplant model, animals received daily treatments of either statin or selective isoprenoid blockade inhibitors to block the four major downstream branches of the mevalonate pathway. TCAD was assessed by morphometric analysis at Day 52. Graft-infiltrating cells, cytokine production, smooth muscle cell proliferation and migration and endothelial cell MHC II expression were detected on Day 7.RESULTS: Atorvastatin and two prenylation inhibitors, NE-10790 and manumycin A, significantly reduced TCAD lesions compared with untreated animals. Perillyl alcohol treatment resulted in a trend toward decreased luminal narrowing. Finally, zaragozic acid (cholesterol blockade only) did not alter TCAD severity. Statins and prenylation inhibitors reduced inflammatory cell allograft recruitment, but did not always correlate with TCAD reduction. Cytokine production was decreased in recipient spleens in all treatment groups. Both in vitro and in vivo IFN-γ-stimulated MHC II expression was decreased in a dose-dependent manner in the atorvastatin, perillyl alcohol and NE-10790 groups. In vitro smooth muscle cell proliferation was decreased in all treatment groups. Finally, in vitro smooth muscle cell migration was decreased in the atorvastatin, NE-10790 and manumycin A groups only.CONCLUSIONS: FPT and GGPT-2 (inhibition) are the key enzymes in the HGM-CoA reductase pathway and most influential in TCAD prevention. TCAD reduction is most closely related to smooth muscle cell migration, but not its anti-inflammatory properties.
KW - Animals
KW - Atorvastatin
KW - Bridged Bicyclo Compounds, Heterocyclic/pharmacology
KW - Coronary Artery Disease/etiology
KW - Diphosphonates/pharmacology
KW - Genes, MHC Class II
KW - Graft Survival
KW - Heart Transplantation/adverse effects
KW - Heptanoic Acids/pharmacology
KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
KW - Immunity, Cellular
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Models, Biological
KW - Muscle, Smooth/cytology
KW - Polyenes/pharmacology
KW - Polyunsaturated Alkamides/pharmacology
KW - Prenylation/drug effects
KW - Pyridines/pharmacology
KW - Pyrroles/pharmacology
KW - Signal Transduction/drug effects
KW - Time Factors
KW - Transplantation, Heterotopic
KW - Tricarboxylic Acids/pharmacology
U2 - 10.1016/j.healun.2011.01.720
DO - 10.1016/j.healun.2011.01.720
M3 - SCORING: Journal article
C2 - 21458297
VL - 30
SP - 761
EP - 769
JO - J HEART LUNG TRANSPL
JF - J HEART LUNG TRANSPL
SN - 1053-2498
IS - 7
ER -
