Treatment with telmisartan attenuates graft arteriosclerosis in murine cardiac allografts.
BACKGROUND
Chronic rejection remains the most prominent cause of graft failure after transplantation. Recently, it was reported that telmisartan can function as a partial agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) in addition to a blocker of angiotensin II receptor. We investigated the effect of telmisartan on chronic rejection.


METHODS
Hearts from Bm12 mice were transplanted into C57BL/6 mice (Class II mismatch), and allografts were harvested at 8 weeks after transplantation. Recipient mice were fed either control chow or chow containing telmisartan (10 mg/kg/day) from 1 day before transplantation. Proliferation assays of smooth muscle cells (SMCs), which were isolated from the aorta of B/6 mice, was performed.


RESULTS
Although severe neo-intimal hyperplasia developed in allografts from control mice fed chow (luminal occlusion 70.9 +/- 6.1%), neo-intimal hyperplasia was significantly attenuated in allografts from mice fed chow containing telmisartan (30.0 +/- 10%, p < 0.001). Expression of interferon (IFN)-gamma and interleukin (IL)-15 mRNAs and matrix metalloproteinase (MMP)-2 in allografts was significantly lower in telmisartan-treated mice than in control mice. Proliferation of smooth muscle cells (SMCs) in response to fetal bovine serum was suppressed significantly by telmisartan (10 micromol/liter). The PPARgamma antagonist blocked telmisartan-induced suppression of SMC proliferation.


CONCLUSIONS
Telmisartan attenuates SMC proliferation via PPARgamma activity and suppresses neo-intimal hyperplasia after transplantation. Telmisartan may be useful for suppressing chronic allograft rejection.
Kosuge
Hisanori
H
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan. kosuge.cvm@tmd.ac.jp
Ishihara
Takashi
T
Haraguchi
Go
G
Maejima
Yasuhiro
Y
Okada
Hiroyuki
H
Saiki
Hitoshi
H
Suzuki
Jun-ichi
J
Isobe
Mitsuaki
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003324:Coronary Artery Disease / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology*; D006965:Hyperplasia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists*; D000077333:Telmisartan; D014184:Transplantation, Homologous; D017540:Tunica Media / Q000276:immunology / Q000473:pathology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D016207:Cytokines; D047495:PPAR gamma; D000077333:Telmisartan