Dichotomous effects of rosiglitazone in transplantation-induced systemic vasodilator dysfunction in rats.
BACKGROUND
Transplantation-induced systemic endothelial dysfunction causes severe cardiovascular morbidity and mortality after transplantation. Interventions that improve systemic endothelial function after transplantation and furthermore reduce intragraft vascular dysfunction might improve graft and patient survival. Treatment with the PPARgamma agonist rosiglitazone is an intervention that potentially fulfills these criteria. In this study, we determined the effect of rosiglitazone treatment on transplantation-induced endothelial dysfunction and vasomotor activity in an experimental model for chronic transplant dysfunction in rats.


METHODS
Lewis abdominal aortic allografts were orthotopically transplanted into Brown Norway recipients that received either regular chow or chow containing rosiglitazone (approximately 4.2 mg/day). Endothelium-dependent (response to metacholine) and total (response to sodium nitrite) vasodilatory responses were determined in autologous thoracic aortic rings using an ex vivo organ bath setup. Measurements were performed 8 weeks after transplantation.


RESULTS
Aortic allografting induced systemic endothelial dysfunction as measured by reduced endothelium-dependent vasodilation in the recipient's vascular system. Rosiglitazone treatment restored endothelium-dependent vasodilatory responses to pretransplantation levels. However, rosiglitazone treatment reduced the total dilatory response despite normalized endothelial function, indicating impairment of vascular smooth muscle cell vasomotor activity.


CONCLUSIONS
Rosiglitazone treatment after allogeneic transplantation restores endothelial function but impairs vascular smooth muscle cell vasomotor activity. This dichotomous effect of rosiglitazone might impede use of rosiglitazone after organ transplantation since this potentially increases cardiovascular risk despite improved endothelial cell function.
Onuta
Geanina
G
Department of Cell Biology, Section Immunology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
Hillebrands
Jan-Luuk
JL
Rienstra
Heleen
H
Boer
Mark Walther
MW
Klatter
Flip A
FA
Navis
Gerjan
G
Rozing
Jan
J
Roks
Anton J M
AJ
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000473:pathology / Q000637:transplantation*; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014184:Transplantation, Homologous / Q000009:adverse effects*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone