Effect of cyclosporine, mycophenolic acid, and rapamycin on the proliferation of rat aortic vascular smooth muscle cells: in vitro study.
Institute for Transplantation Research, Yonsei University College of Medicine, Seoul, South Korea.Transplantation Proceedings (Impact Factor: 0.95). 12/2000; 32(7):2026-7. DOI:10.1016/S0041-1345(00)01542-6
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ABSTRACT: The synthesis of extracellular matrix (ECM) in mesangial cells (MCs) plays important roles in the development and progression of renal diseases, including chronic allograft nephropathy. Mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase2 (IMPDH2), suppresses MC proliferation and ECM synthesis. However, the exact inhibitory mechanism of MPA on MCs has not been clearly elucidated. In this study we compared the inhibitory effects of MPA and IMPDH2 reduction [by using small interfering RNA (siRNA)] on oleic acid (OA)-induced fibronectin secretion and cellular reactive oxygen species (ROS) in mouse MCs. Growth-arrested MCs were stimulated with OA in the presence or absence of MPA, IMPDH2 siRNA, N-acetylcysteine (NAC), transforming growth factorbeta (TGF-β) antibody or exogenous guanosine. Fibronectin secretion into the medium was examined by Western blot, dichlorodihydrofluorescein (DCF)-sensitive cellular ROS by fluorescence-activated cell scanning (FACS), TGF-β levels in the media by enzyme-linked immunosorbent assay (ELISA). OA increased fibronectin secretion, TGF-β and cellular ROS levels. A TGF-β neutralizing antibody effectively suppressed OA-induced fibronectin secretion. NAC and MPA completely suppressed OA-induced fibronectin secretion and decreased the levels of TGF-β and cellular ROS. However, IMPDH2 siRNA partly inhibited OA-induced MC activation. Exogenous guanosine successfully reversed the inhibitory effects of IMPDH2 siRNA on OA-induced MC activation. Pleiotropic inhibitory effect of MPA on OA-induced mouse MC activation was mediated via its antioxidant effect on cellular ROS production and partly via inhibition of IMPDH2 itself. Our results implicate ROS as an alternative therapeutic target for the prevention of hyperlipidemia-related glomerulopathy, chronic allograft nephropathy, and subsequent graft loss.Pediatric Nephrology 04/2012; 24(4):737-745. · 2.94 Impact Factor
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ABSTRACT: In this 12-month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNI-therapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 ± 4.0 vs. 0.3 ± 3.1%; p = 0.02) and necrotic component (6.5 ± 8.5 vs. 1.1 ± 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.American Journal of Transplantation 09/2012; 12(10):2700-2709. · 6.19 Impact Factor
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ABSTRACT: Nanoparticles (NPs) possess several advantages as a carrier system for intracellular delivery of therapeutic agents. Rapamycin is an immunosuppressive agent which also exhibits marked antiproliferative properties. We investigated whether rapamycin-loaded NPs can reduce neointima formation of vein graft disease in a rat model. Poly(lactic-co-glycolic acid) (PLGA) NPs-containing rapamycin was prepared using an oil/water solvent evaporation technique. The size and morphology of the NP were determined by dynamic light scattering methodology and electron microscopy. In vitro cytotoxicity of blank, rapamycin-loaded PLGA NPs was studied using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Excised rat jugular vein was treated ex vivo with blank NPs, or rapamycin-loaded NPs, and then interposed back into the carotid artery position using a cuff technique. Grafts were harvested for 21 days and subjected to morphometric analysis as well as immunohistochemical analysis and Western blotting. Rapamycin was efficiently loaded in PLGA NPs with an encapsulation efficiency of 87.6%. The average diameter of NPs was 180.3 nm. The NPs-containing rapamycin at 1 ng/mL significantly inhibited vascular smooth muscular cells proliferation. Measurement of rapamycin levels in vein grafts showed that the concentration of rapamycin in vein grafts at 3 weeks after grafting was 0.9 ± 0.1 μg/g. In grafted veins without treatment, intima-media thickness was 300.4 ± 181.5 μm at 21 days after grafting, whereas veins treated with rapamycin-loaded NPs showed a reduction of intimal-media thickness of 150.2 ± 62.5 μm (p = 0.001). Cell proliferation was measured by proliferating cell nuclear antigen immunohistochemistry staining. As expected, proliferating cell nuclear antigen index declined from 83.4% ± 7.4% to 66.2% ± 4.5% in vein grafts after 3 weeks (p = 0.002). Platelet endothelial cell adhesion molecule (PECAM-1/CD31) staining was used to measure luminal endothelial coverage in grafts and indicated a high level of endothelialization at 21 days after grafting, with no significant effect of blank or rapamycin-loaded NPs group. Western blot analysis showed that treatment with rapamycin-loaded PLGA NPs markedly attenuated phosphorylation and activation of S6 kinase 1 phosphorylation and inactivation of 4E (eIF4E)-binding protein 1, both in vascular smooth muscular cells and vein grafts at 7 and 21 days after grafting. We conclude that sustained-release rapamycin from rapamycin-loaded NPs inhibits vein graft thickening without affecting the endothelial cells in rat carotid vein-to-artery interposition grafts; thus, this may be a promising therapy for the treatment of vein graft disease.Annals of Vascular Surgery 05/2011; 25(4):538-46. · 0.99 Impact Factor
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