mna-715 and Hyperplasia

Venous grafts are commonly used to treat drug-resistant coronary artery disease, although long-term functionality is limited because of proliferation and migration of smooth muscle cells (SMC). As proliferating SMC are particularly susceptible for the stimulating effects of cytomegalovirus (CMV), we hypothesized that CMV infection may enhance cell proliferation and graft failure. Furthermore, we evaluated the potential of FK778 to prevent intimal hyperplasia. Apart from its antiviral properties, FK778 is a new immunosuppressive agent which may also affect SMC proliferation, making it an interesting drug to prevent (CMV-enhanced) venous graft intimal hyperplasia.. Epigastric vein-to-common femoral artery interposition grafts were placed in four groups of 10 rats each. Rats received either FK778 (oral treatment, 15 mg/kg), were infected with CMV (1.25 x 10(6) plaque-forming units) or were both treated and infected.. CMV infection resulted in a significant increase in intimal and medial cross-sectional area and medial wall thickness of the vein grafts. This effect was diminished by administration of FK778. Moreover, FK778 treatment alone resulted in a significant decrease in neointimal area and percentage of stenosis versus the control group.. These data suggest a role of CMV in venous graft failure. Also, our results suggest a prospective role for the new immunosuppressive drug FK778 in the prevention of (CMV-mediated) vein graft intimal hyperplasia.

Topics: Alkynes; Animals; Anti-Inflammatory Agents; Antiviral Agents; Herpesviridae Infections; Hyperplasia; Immunosuppressive Agents; Isoxazoles; Male; Muromegalovirus; Nitriles; Rats; Transplants; Tunica Intima

To investigate the efficacy of the malononitrilamide FK778 to prevent vascular smooth muscle cell (SMC) migration/proliferation, and vascular fibrosis, the key events in restenosis development using in vivo and in vitro studies.. Since the high rate of restenosis after percutaneous transluminal coronary angioplasty limited its long-term success, the implementation of locally delivered antiproliferative/immunosuppressive agents became advantageous.. Rats underwent balloon denudation of the abdominal aorta and received sirolimus, tacrolimus, or FK778 for 28 days in varying doses. Aortas were harvested for histologic evaluation, profibrotic gene expression, and organ chamber studies. Antifibrotic, antiproliferative and antimigratory effects of the immunosuppressants were further evaluated in vitro.. Histology of untreated animals revealed marked intimal hyperplasia with moderate luminal obliteration. Neointima formation was dose-dependently attenuated by all three agents with FK778 and sirolimus being most efficacious. Organ chamber relaxation studies showed a leftward shift of the nitroglycerin and the acetylcholine dose-responses in all treatment groups, indicating diminished endothelial dysfunction. In vivo, only FK778 treatment revealed a significant downregulation of the TGF-beta/vasorin system which could be explained by upregulation of the TGF-beta-inhibitory mediator SMAD7. In vitro, FK778 showed most potent antiproliferative and antimigratory effects on SMC compared with sirolimus and tacrolimus. Only the antiproliferative effect of FK778 was due to pyrimidine synthesis blockade and could be reversed by uridine supplementation.. The malononitrilamide FK778 proved highly efficacious against restenosis development by targeting two major components of intimal hyperplasia: SMC proliferation/migration and vascular fibrosis. Thus, the introduction of malononitrilamide-loaded stents may be a promising effort for future strategies.

Topics: Alkynes; Animals; Aorta, Abdominal; Carrier Proteins; Cell Movement; Cell Proliferation; Endothelium, Vascular; Graft Occlusion, Vascular; Hyperplasia; Immunosuppressive Agents; Isoxazoles; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitriles; Rats; Rats, Inbred Lew; RNA, Messenger; Sirolimus; Smad7 Protein; Tacrolimus; Transforming Growth Factor beta1; Tunica Intima; Vasodilation; Vasodilator Agents

To test the efficacy of limited oral administration of the new leflunomide analogue FK778 for suppression of neointima proliferation in a double-injury restenosis model in the rat.. For induction of aortic lesions, silicon cuffs were placed operatively around the infrarenal aortas of Lewis rats. After 21 days, the aortic cuffs were removed and the lesions were dilated with 2-F Fogarty catheters inserted via the left common carotid artery. The novel immunosuppressant FK778 was administered at a dose of 5 mg/kg body weight (group 1) or 15 mg/kg body weight (group 2) in a total of 38 animals. For both doses, three different periinterventional time periods, each with a 5-day course of oral FK778, were defined as follows: (i) days -2 to 2, (ii) days 1-5, and (iii) days 7-11, with six or seven rats in each group. After 3 weeks, intima/media ratios were assessed morphometrically and immunohistochemistry for quantification of intimal alpha-actin expression was performed.. In both dose groups, there was a trend toward inhibition of neointima formation when the 5-day course of FK778 was started before or 1 day after the intervention. However, in the lower-dose group, inhibition of neointima was not statistically significant regardless of the time frame of treatment (groups 1a-c). With the higher dose, suppression of intimal hyperplasia was significant when FK778 was administered between days 1 and 5 after angioplasty (group 2b; P<.01). Expression of alpha-actin in the intima of FK778-treated rats was significantly reduced when the drug was started 2 days before angioplasty in group 1a (P<.05) or 1 day after angioplasty in both dosage groups (group 1b, P<.01; group 2b, P<.05).. In the double-injury rat model presented, balloon-mediated proliferation of smooth muscle cells in the intima with consecutive intimal thickening was influenced by FK778 in a dose-dependent manner. However, long-term studies are needed to exclude a delay of vascular healing in this particular model.

Topics: Actins; Administration, Oral; Alkynes; Angioplasty, Balloon; Animals; Disease Models, Animal; Hyperplasia; Immunohistochemistry; Immunosuppressive Agents; Isoxazoles; Male; Muscle, Smooth, Vascular; Nitriles; Rats; Rats, Inbred Lew; Tunica Intima