Mycophenolic Acid Inhibits Cell Proliferation and Extracellular Matrix Synthesis in Rat Vascular Smooth Muscle Cells Through Direct and Indirect Inhibition of Cellular Reactive Oxygen Species

Park, Jehyun; Chang, Hye Kyung; Ha, Hunjoo; Kim, Myoung Soo; Ahn, Hyung Joon; Kim, Yu Seun

doi:10.1016/j.jss.2007.09.011

Cited by 14 publications

(9 citation statements)

References 34 publications

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“…As a possible mechanism, we previously suggested that MPA directly and indirectly inhibits PDGF-induced cellular ROS in VSMCs [30]. Our study described now demonstrated that MPA also completely inhibited OA-induced cellular ROS in MCs, whereas IMPDH2 siRNA partly suppressed OA-induced cellular ROS.…”

Section: Discussionsupporting

confidence: 52%

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Mycophenolic acid inhibits oleic acid-induced mesangial cell activation through both cellular reactive oxygen species and inosine monophosphate dehydrogenase 2 pathways

Huh

Ahn

Park³

et al. 2009

Pediatr Nephrol

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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 dehydrogenase 2 (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 factor beta (TGF-beta) 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-beta levels in the media by enzyme-linked immunosorbent assay (ELISA). OA increased fibronectin secretion, TGF-beta and cellular ROS levels. A TGF-beta neutralizing antibody effectively suppressed OA-induced fibronectin secretion. NAC and MPA completely suppressed OA-induced fibronectin secretion and decreased the levels of TGF-beta 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.

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Section: Discussionsupporting

confidence: 52%

“…We previously reported that MPA inhibited VSMC and MC proliferation and ECM synthesis [27,29,30]. However, IMPDH2 is only partly involved in the inhibitory action of MPA on mesenchymal cells [31].…”

Section: Introductionmentioning

confidence: 99%

Mycophenolic acid inhibits oleic acid-induced mesangial cell activation through both cellular reactive oxygen species and inosine monophosphate dehydrogenase 2 pathways

Huh

Ahn

Park³

et al. 2009

Pediatr Nephrol

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“…ROS in VSMCs regulate not only cellular migration and proliferation but also accumulation of matrix proteins such as collagen [33,34]. As shown by Masson’s trichrome staining in Fig.…”

Section: Resultsmentioning

confidence: 99%

8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation

Huh

Son

Lee

et al. 2012

Free Radical Biology and Medicine

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8-Hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress, has been recently rediscovered to inhibit Rac1 in neutrophils and macrophages, thereby inhibiting Rac1-linked functions of these cells, including reactive oxygen species production through NADPH oxidase activation, phagocytosis, chemotaxis, and cytokine release. In vascular smooth muscle cells (VSMCs), reactive oxygen species also induce abnormal proliferation and migration leading to progression of atherosclerosis. Based upon the involvement of reactive oxygen species in phagocytic cells and VSMCs during the atherosclerotic process, we hypothesized that 8-OHdG could have antiatherosclerotic action and tested this hypothesis in an experimentally induced atherosclerosis in mice. Partially ligated ApoE knockout mice, a more physiologically relevant model of low and oscillatory flow, developed an advanced lesion in 2 weeks, and orally administered 8-OHdG significantly reduced plaque formation along with reduced superoxide formation, monocyte/macrophage infiltration, and extracellular matrix (ECM) accumulation. The effects of 8-OHdG observed in primary VSMCs were consistent with the in vivo effects of 8-OHdG and were inhibitory to angiotensin II or platelet-derived growth factor-induced production of reactive oxygen species, proliferation, migration, and ECM production. Also, angiotensin II-induced Rac1 activity in VSMCs was significantly inhibited by 8-OHdG, and transfection of constitutively active Rac1 reversed the inhibitory effect of 8-OHdG on VSMC activation. Molecular docking study showed that 8-OHdG stabilizes Rac1–GEF complex, indicating the physical contact of 8-OHdG with Rac1. These findings highly suggest that the antiatherosclerotic effect of 8-OHdG is mediated by inhibition of Rac1 activity. In conclusion, our results show a novel action of orally active 8-OHdG in suppressing atherosclerotic plaque formation in vivo and VSMC activation in vitro through inhibition of Rac1, which emphasizes a new therapeutic avenue to benefit atherosclerosis.

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“…Although the additional benefit of adding MMF to the immunosuppressive drug regimen after solid organ transplantation has unequivocally been proven, its mechanism of action might include other points of attack than just inhibition of proliferation. For instance, its ability to alter leucocyte–endothelial adhesion and inhibition of platelet‐derived growth factor induced vascular smooth muscle cell proliferation by directly scavenging H 2 O 2 may add to overall immunosuppressive capacity [21,22].…”

Section: Discussionmentioning

confidence: 99%

Mycophenolate mofetil inhibits T-cell proliferation in kidney transplant recipients without lowering intracellular dGTP and GTP

Sankatsing¹,

Prins²,

Yong³

et al. 2008

Transplant International

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Summary To study if mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), indeed inhibits T‐cell proliferation in kidney transplant recipients by lowering intracellular deoxyguanosine triphosphate (dGTP) and guanosine triphosphate (GTP) levels. Blood was drawn from 11 kidney transplant recipients. Ex vivo T‐cell proliferation was measured by stimulation with phytohemagglutin (PHA) and anti‐CD3 monoclonal antibody (mAb). Plasma MPA levels and intracellular dGTP and GTP in peripheral blood mononuclear cells were measured. MMF induces a significant decrease in T‐lymphocyte proliferation at all time points (i.e. 24 h, 10 days and 8 weeks) after stimulation with both PHA (P = 0.001, 0.002 and 0.013 respectively) and anti‐CD3 mAb (P = 0.004, 0.004 and 0.005 respectively). There was no significant change in intracellular dGTP (P = 0.31, 0.16 and 0.35) or GTP levels (P = 0.99, 0.32 and 0.49) between baseline and day 1, day 10 or week 8. All MPA levels were above the minimal required concentration for the inhibition of lymphocyte proliferation. MMF inhibits T‐lymphocyte proliferation in kidney transplant recipients without lowering intracellular dGTP or GTP levels. This suggests another mechanism underlying its immunosuppressive capacity.

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Mycophenolic Acid Inhibits Cell Proliferation and Extracellular Matrix Synthesis in Rat Vascular Smooth Muscle Cells Through Direct and Indirect Inhibition of Cellular Reactive Oxygen Species

Cited by 14 publications

References 34 publications

Mycophenolic acid inhibits oleic acid-induced mesangial cell activation through both cellular reactive oxygen species and inosine monophosphate dehydrogenase 2 pathways

Mycophenolic acid inhibits oleic acid-induced mesangial cell activation through both cellular reactive oxygen species and inosine monophosphate dehydrogenase 2 pathways

8-Hydroxy-2-deoxyguanosine prevents plaque formation and inhibits vascular smooth muscle cell activation through Rac1 inactivation

Mycophenolate mofetil inhibits T-cell proliferation in kidney transplant recipients without lowering intracellular dGTP and GTP

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