Candesartan cilexetil reduces graft arteriosclerosis in aortic transplantation model in rat.
To date established treatment of transplant arteriosclerosis is basically missing and there is a need for new therapeutic approaches. Angiotensin II (Ang II) and Ang II receptor type 1 (AT) are present in the vascular wall. Blocking of the AT1 receptor by pharmacological agents may inhibit damaging effects of Ang II on endothelial and smooth muscle cells. The purpose of the study was to evaluate the effect of the AT1 receptor blocker Candesartan cilexetil on the development of graft arteriosclerosis in a rat aortic transplant model. Two strain combinations were used for aortic transplantation: DA to PVG; and PVG to PVG. The animals received Candesartan cilexetil treatment (9.5 + 1.4 mg/kg/day) for 8 weeks. Candesartan cilexetil treatment reduced neointimal formation both in allografts (Qint 30.2 +/- 8.8% vs. 22.1 +/- 8.7%, P < 0.05) and in isografts (Qint 15.5 +/- 4.4% vs. 6.7 +/- 3.3%, P = 0.0001). Blocking of the AT1 receptor signalling by Candesartan cilexetil was also associated with a reduced expression of TGF-beta1. Macrophage infiltration was not affected by the treatment. Candesartan cilexetil treatment leads to reduced neointimal formation in aortic transplant. The positive effect of the drug might be partly explained by a reduction of TGF-beta1 expression in the grafts. Candesartan treatment may provide another possibility for prevention of transplant arteriosclerosis and chronic rejection.
Zezina
L
L
Department of Medical Sciences, Uppsala University, Sweden. Lilian.Zezina@medsci.uu.se
Larsson
E
E
Fellström
B
B
D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure; D004353:Drug Evaluation, Preclinical; D006084:Graft Rejection / Q000150:complications*; D006965:Hyperplasia; D008264:Macrophages / Q000473:pathology; D008297:Male; D023421:Models, Animal; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology; D013777:Tetrazoles; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C077793:candesartan cilexetil