Lp. Perrault et al., Impairment of G-protein-mediated signal transduction in the porcine coronary endothelium during rejection after heart transplantation, CARDIO RES, 43(2), 1999, pp. 457-470
Citations number
45
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background: Endothelial dysfunction is an early event leading to atheroscle
rosis. It also occurs after orthotopic heart transplantation and can be use
d to predict the development of intimal hyperplasia in the coronary artery
wall. The present study was designed to assess the time course and specific
alterations underlying endothelial dysfunction due to rejection after hear
t transplantation. Methods: A porcine model of heterotopic heart transplant
ation was used. Preoperative serum typing for the class I antigen of the sw
ine lymphocyte alloantigen was performed to ensure compatibility for this a
ntigen. This permitted survival of the graft with a low grade rejection wit
hout immunosuppression. Rings (with or without endothelium) of epicardial c
oronary arteries of native and transplanted hearts were studied in organ ch
ambers filled with modified Krebs-Ringer bicarbonate solution and compared
1, 30 and 60 days after transplantation. Results: Myocardial contractility
was normal in all grafts studied at 60 days after transplantation and all c
oronary arteries were patent. Myocardial biopsies showed the progression of
rejection from day 1 to day 60 after implantation. All endothelium-depende
nt relaxations were normal one day after transplantation. Endothelium-depen
dent relaxations to serotonin and to the alpha(2)-adrenergic agonist UK1430
4 (which both activate receptors coupled to Gi-proteins) and to sodium fluo
ride (a direct activator of G-proteins) were decreased 30 days after transp
lantation, while those to the calcium ionophore, A23187, and bradykinin wer
e shifted to the right and those to ADP were normal. At 60 days, endotheliu
m-dependent relaxations mediated by the Gi-protein pathway were decreased f
urther while the concentration-relaxation curves to the other agonists were
further shifted to the right. Endothelium-independent relaxations to the n
itric oxide donor, Sin-1, were progressively reduced at 30 and 60 days, but
maximal relaxations were maintained at 60 days. Histomorphometric studies
showed a progressive increase in the percentage of coronary rings with inti
mal thickening from day 1 to day 60 after transplantation. Conclusions: The
progressive endothelial dysfunction reported in this model of accelerated
coronary atherosclerosis after transplantation without immunosuppression in
volves preferentially the pertussis-toxin-sensitive Gi-protein-mediated pat
hway. Endothelium-independent relaxations are decreased at 60 days, as are
all other endothelium-dependent relaxations. Decreased endothelium-dependen
t vasodilatation may contribute to the development of coronary graft vascul
opathy. (C) 1999 Published by Elsevier Science B.V. All rights reserved.