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Lovastatin inhibits oxidized low-density lipoprotein-induced plasminogen activator inhibitor and transforming growth factor-beta1 expression via a decrease in Ras/extracellular signal-regulated kinase activity in mesangial cells.
Transl Res. 2008 Jan; 151(1):27-35.TR

Abstract

Oxidized low-density lipoprotein (Ox-LDL) might be involved in the progression of renal disease. Ox-LDL stimulation of plasminogen activator inhibitor-1 (PAI-1) expression via transforming growth factor-beta (TGF-beta)/Smad signaling in mesangial cells required activation of extracellular signal-regulated kinase (ERK). Mevalonate depletion by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, decreases the levels of farnesyl pyrophosphate (FPP) for isoprenylation of Ras. We postulate that statins may ameliorate the Ox-LDL-induced mesangial matrix accumulation by inhibiting Ras/ERK activation with subsequent downregulation of TGF-beta target genes. Quiescent mesangial cells were incubated for 18 h with and without the presence of lovastatin before 50 microg/mL of Ox-LDL treatment for 1 h. Lovastatin inhibited markedly the stimulatory effects of Ox-LDL on ERK1/2 activation, nuclear Smad3 expression, TGF-beta1 and PAI-1 mRNA and protein expression, and PAI-1 luciferase activity. These inhibitory effects of lovastatin were reversed almost completely by mevalonate or FPP. Similar to lovastatin, FTI-277, which is an inhibitor of Ras farnesylation, decreased the Ox-LDL-induced activation of ERK/Smad3 and induction of TGF-beta1/PAI-1. These results indicate that lovastatin prevents the Ox-LDL-induced Ras/ERK activation that results in inhibition of Smad3 activation in mesangial cells with subsequent downregulation of TGF-beta target genes. Thus, statins seem to have antifibrotic effects through their anti-TGF-beta response that are relevant in the treatment of chronic renal disease with dyslipidemia.

Authors+Show Affiliations

Department of Pathology, Seoul National University College of Medicine, Chongno-gu, Yongon-dong 28, Seoul, Korea.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18061125

Citation

Song, Chi Young, et al. "Lovastatin Inhibits Oxidized Low-density Lipoprotein-induced Plasminogen Activator Inhibitor and Transforming Growth Factor-beta1 Expression Via a Decrease in Ras/extracellular Signal-regulated Kinase Activity in Mesangial Cells." Translational Research : the Journal of Laboratory and Clinical Medicine, vol. 151, no. 1, 2008, pp. 27-35.
Song CY, Kim BC, Lee HS. Lovastatin inhibits oxidized low-density lipoprotein-induced plasminogen activator inhibitor and transforming growth factor-beta1 expression via a decrease in Ras/extracellular signal-regulated kinase activity in mesangial cells. Transl Res. 2008;151(1):27-35.
Song, C. Y., Kim, B. C., & Lee, H. S. (2008). Lovastatin inhibits oxidized low-density lipoprotein-induced plasminogen activator inhibitor and transforming growth factor-beta1 expression via a decrease in Ras/extracellular signal-regulated kinase activity in mesangial cells. Translational Research : the Journal of Laboratory and Clinical Medicine, 151(1), 27-35.
Song CY, Kim BC, Lee HS. Lovastatin Inhibits Oxidized Low-density Lipoprotein-induced Plasminogen Activator Inhibitor and Transforming Growth Factor-beta1 Expression Via a Decrease in Ras/extracellular Signal-regulated Kinase Activity in Mesangial Cells. Transl Res. 2008;151(1):27-35. PubMed PMID: 18061125.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lovastatin inhibits oxidized low-density lipoprotein-induced plasminogen activator inhibitor and transforming growth factor-beta1 expression via a decrease in Ras/extracellular signal-regulated kinase activity in mesangial cells. AU - Song,Chi Young, AU - Kim,Bong Cho, AU - Lee,Hyun Soon, Y1 - 2007/11/01/ PY - 2007/08/01/received PY - 2007/09/26/revised PY - 2007/09/27/accepted PY - 2007/12/7/pubmed PY - 2008/1/11/medline PY - 2007/12/7/entrez SP - 27 EP - 35 JF - Translational research : the journal of laboratory and clinical medicine JO - Transl Res VL - 151 IS - 1 N2 - Oxidized low-density lipoprotein (Ox-LDL) might be involved in the progression of renal disease. Ox-LDL stimulation of plasminogen activator inhibitor-1 (PAI-1) expression via transforming growth factor-beta (TGF-beta)/Smad signaling in mesangial cells required activation of extracellular signal-regulated kinase (ERK). Mevalonate depletion by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, decreases the levels of farnesyl pyrophosphate (FPP) for isoprenylation of Ras. We postulate that statins may ameliorate the Ox-LDL-induced mesangial matrix accumulation by inhibiting Ras/ERK activation with subsequent downregulation of TGF-beta target genes. Quiescent mesangial cells were incubated for 18 h with and without the presence of lovastatin before 50 microg/mL of Ox-LDL treatment for 1 h. Lovastatin inhibited markedly the stimulatory effects of Ox-LDL on ERK1/2 activation, nuclear Smad3 expression, TGF-beta1 and PAI-1 mRNA and protein expression, and PAI-1 luciferase activity. These inhibitory effects of lovastatin were reversed almost completely by mevalonate or FPP. Similar to lovastatin, FTI-277, which is an inhibitor of Ras farnesylation, decreased the Ox-LDL-induced activation of ERK/Smad3 and induction of TGF-beta1/PAI-1. These results indicate that lovastatin prevents the Ox-LDL-induced Ras/ERK activation that results in inhibition of Smad3 activation in mesangial cells with subsequent downregulation of TGF-beta target genes. Thus, statins seem to have antifibrotic effects through their anti-TGF-beta response that are relevant in the treatment of chronic renal disease with dyslipidemia. SN - 1931-5244 UR - https://www.unboundmedicine.com/medline/citation/18061125/Lovastatin_inhibits_oxidized_low_density_lipoprotein_induced_plasminogen_activator_inhibitor_and_transforming_growth_factor_beta1_expression_via_a_decrease_in_Ras/extracellular_signal_regulated_kinase_activity_in_mesangial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1931-5244(07)00253-8 DB - PRIME DP - Unbound Medicine ER -