Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase

1993 ◽  
Vol 101 (1) ◽  
pp. 117-125 ◽  
Author(s):  
Alberto Corsini ◽  
Maria Mazzotti ◽  
Marco Raiteri ◽  
Maurizio R. Soma ◽  
Giulio Gabbiani ◽  
...  
Keyword(s):  
Mevalonate Pathway ◽  
In Vitro Studies ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Myocyte Proliferation ◽  
Proliferation In Vitro

scholarly journals Identification, Evolution, and Essentiality of the Mevalonate Pathway for Isopentenyl Diphosphate Biosynthesis in Gram-Positive Cocci

2000 ◽  
Vol 182 (15) ◽  
pp. 4319-4327 ◽  
Author(s):  
E. Imogen Wilding ◽  
James R. Brown ◽  
Alexander P. Bryant ◽  
Alison F. Chalker ◽  
David J. Holmes ◽  
...  
Keyword(s):  
Mevalonate Pathway ◽  
Genomic Analysis ◽  
Eukaryotic Cell ◽  
Infection Model ◽  
Isopentenyl Diphosphate ◽  
Gram Positive ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Gram Positive Cocci

ABSTRACT The mevalonate pathway and the glyceraldehyde 3-phosphate (GAP)–pyruvate pathway are alternative routes for the biosynthesis of the central isoprenoid precursor, isopentenyl diphosphate. Genomic analysis revealed that the staphylococci, streptococci, and enterococci possess genes predicted to encode all of the enzymes of the mevalonate pathway and not the GAP-pyruvate pathway, unlike Bacillus subtilis and most gram-negative bacteria studied, which possess only components of the latter pathway. Phylogenetic and comparative genome analyses suggest that the genes for mevalonate biosynthesis in gram-positive cocci, which are highly divergent from those of mammals, were horizontally transferred from a primitive eukaryotic cell. Enterococci uniquely encode a bifunctional protein predicted to possess both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and acetyl-CoA acetyltransferase activities. Genetic disruption experiments have shown that five genes encoding proteins involved in this pathway (HMG-CoA synthase, HMG-CoA reductase, mevalonate kinase, phosphomevalonate kinase, and mevalonate diphosphate decarboxylase) are essential for the in vitro growth of Streptococcus pneumoniae under standard conditions. Allelic replacement of the HMG-CoA synthase gene rendered the organism auxotrophic for mevalonate and severely attenuated in a murine respiratory tract infection model. The mevalonate pathway thus represents a potential antibacterial target in the low-G+C gram-positive cocci.

scholarly journals Mevalonate Prevents Lovastatin-Induced Apoptosis in Medulloblastoma Cell Lines

1999 ◽  
Vol 26 (4) ◽  
pp. 305-310 ◽  
Author(s):  
Wei Wang ◽  
Robert J.B. Macaulay
Keyword(s):  
Cell Lines ◽  
Mevalonate Pathway ◽  
Critical Duration ◽  
Northern Analysis ◽  
Hmg Coa Reductase ◽  
Medulloblastoma Cell ◽  
Induced Apoptosis ◽  
Coa Reductase ◽  
Medulloblastoma Cell Lines

Background:3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) is a key rate-limiting enzyme in the mevalonate pathway, which generates precursors for cholesterol biosynthesis and the production of non-steroidal mevalonate derivatives that are involved in a number of growth-regulatory processes. We have reported that lovastatin, a competitive inhibitor of HMG-CoA reductase, not only inhibits medulloblastoma proliferationin vitro, but also induces near-complete cell death via apoptosis. The present study explores some of the pathways which may be involved in lovastatin-induced apoptosis.Methods:Medulloblastoma cell lines were exposedin vitroto lovastatin with or without mevalonate, and document the effects using morphology, flow cytometry, DNA electrophoresis and Northern analysis.Results:1) Mevalonate prevents apoptosis when co-incubated with lovastatin, or when administered to lovastatin-pretreated cells. 2) Mevalonate restores the lovastatin-arrested cell cycle, allowing S phase entry. 3) Mevalonate does not prevent lovastatin-induced apoptosis after a critical duration of lovastatin pretreatment. For cell lines Daoy and UW228 this was 24 hours, and for D283 Med and D341 Med it was 48 hours. 4) Increases in HMG-CoA reductase mRNA levels induced by lovastatin are abrogated by co-incubation with lovastatin and mevalonate.Conclusion:These results confirm that lovastatin inhibition of this enzyme results in blockage of the mevalonate pathway, and that such a block is a critical step in the mechanism of lovastatin-induced apoptosis.

In vitro antioxidant, antiglycation, and enzymatic inhibitory activity against α-glucosidase, α-amylase, lipase and HMG-CoA reductase of Terminalia boivinii Tul.

2021 ◽  
pp. 102235
Author(s):  
Bongani Sicelo Dlamini ◽  
Carlos Eduardo Hernandez ◽  
Chiy-Rong Chen ◽  
Wen-Ling Shih ◽  
Jue-Liang Hsu ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Hmg Coa Reductase ◽  
Coa Reductase

Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3354-3362 ◽  
Author(s):  
Niels W. C. J. van de Donk ◽  
Marloes M. J. Kamphuis ◽  
Berris van Kessel ◽  
Henk M. Lokhorst ◽  
Andries C. Bloem
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Mevalonate Pathway ◽  
Cytochrome C Release ◽  
Hmg Coa Reductase ◽  
Myeloma Cells ◽  
Protein Levels ◽  
Geranylgeranyl Transferase ◽  
Induced Apoptosis ◽  
Coa Reductase

AbstractHMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The inhibition of HMG-CoA reductase by lovastatin induced apoptosis in plasma cell lines and tumor cells from patients with multiple myeloma. Here we show that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. In addition, the inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) induced the apoptosis of myeloma cells. Apoptosis triggered by the inhibition of geranylgeranylation was associated with reduction of Mcl-1 protein expression, collapse of the mitochondrial transmembrane potential, expression of the mitochondrial membrane protein 7A6, cytochrome c release from mitochondria into the cytosol, and stimulation of caspase-3 activity. These results imply that protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression. Our results show that pharmacologic agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma.

scholarly journals An autonomous, but INSIG-modulated, role for the Sterol Sensing Domain in mallostery-regulated ERAD of yeast HMG-CoA reductase

2020 ◽  
pp. jbc.RA120.015910
Author(s):  
Margaret A Wangeline ◽  
Randolph Y Hampton
Keyword(s):  
Binding Site ◽  
Quaternary Structure ◽  
Limited Proteolysis ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Level Analysis

HMG-CoA reductase (HMGR) undergoes feedback-regulated degradation as part of sterol pathway control. Degradation of the yeast HMGR isozyme Hmg2 is controlled by the sterol pathway intermediate GGPP, which causes misfolding of Hmg2, leading to degradation by the HRD pathway; we call this process mallostery. We evaluated the role of the Hmg2 sterol sensing domain (SSD) in mallostery, as well as the involvement of the highly conserved INSIG proteins. We show that the Hmg2 SSD is critical for regulated degradation of Hmg2 and required for mallosteric misfolding of GGPP as studied by in vitro limited proteolysis. The Hmg2 SSD functions independently of conserved yeast INSIG proteins, but its function was modulated by INSIG, thus imposing a second layer of control on Hmg2 regulation. Mutant analyses indicated that SSD-mediated mallostery occurred prior to and independent of HRD-dependent ubiquitination. GGPP-dependent misfolding was still extant but occurred at a much slower rate in the absence of a functional SSD, indicating that the SSD facilitates a physiologically useful rate of GGPP response, and implying that the SSD is not a binding site for GGPP. Non-functional SSD mutants allowed us to test the importance of Hmg2 quaternary structure in mallostery:  a non-responsive Hmg2 SSD mutant strongly suppressed regulation of a co-expressed, normal Hmg2. Finally, we have found that GGPP-regulated misfolding occurred in detergent-solubilized Hmg2, a feature that will allow next-level analysis of the mechanism of this novel tactic of ligand-regulated misfolding.

scholarly journals An HMG-CoA Reductase Inhibitor, Cerivastatin, Suppresses Growth of Macrophages Expressing Matrix Metalloproteinases and Tissue Factor In Vivo and In Vitro

Circulation ◽  
2001 ◽  
Vol 103 (2) ◽  
pp. 276-283 ◽  
Author(s):  
Masanori Aikawa ◽  
Elena Rabkin ◽  
Seigo Sugiyama ◽  
Sami J. Voglic ◽  
Yoshihiro Fukumoto ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Tissue Factor ◽  
Reductase Inhibitor ◽  
Hmg Coa Reductase ◽  
Hmg Coa Reductase Inhibitor ◽  
Coa Reductase

scholarly journals Bark Extracts of Ceylon Cinnamon Possess Antilipidemic Activities and Bind Bile Acids In Vitro

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Walimuni Prabhashini Kaushalya Mendis Abeysekera ◽  
Sirimal Premakumara Galbada Arachchige ◽  
Wanigasekera Daya Ratnasooriya
Keyword(s):  
Bile Acids ◽  
Scientific Evidence ◽  
Ethanol Extract ◽  
Cholesterol Esterase ◽  
Hmg Coa Reductase ◽  
Cinnamon Bark ◽  
Ceylon Cinnamon ◽  
Inhibitory Activities ◽  
Coa Reductase

Ethanol (95%) and dichloromethane : methanol (1 : 1) bark extracts of authenticated Ceylon cinnamon were investigated for range of antilipidemic activities (ALA): HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities and bile acids binding in vitro. Individual compounds in bark extracts were also evaluated. Bark extracts showed ALA in all the assays studied. The IC50 (μg/mL) values ranged within 153.07±8.38–277.13±32.18, 297.57±11.78–301.09±4.05, 30.61±0.79–34.05±0.41, and 231.96±9.22–478.89±9.27, respectively, for HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities. The bile acids binding (3 mg/mL) for taurocholate, glycodeoxycholate, and chenodeoxycholate ranged within 19.74±0.31–20.22±0.31, 21.97±2.21–26.97±1.61, and 16.11±1.42–19.11±1.52%, respectively. The observed ALA were moderate compared to the reference drugs studied. Individual compounds in bark extracts ranged within 2.14±0.28–101.91±3.61 and 0.42±0.03–49.12±1.89 mg/g of extract. Cinnamaldehyde and gallic acid were the highest and the lowest among the tested compounds. The ethanol extract had highest quantity of individual compounds and ALA investigated. Properties observed indicate usefulness of Ceylon cinnamon bark in managing hyperlipidemia and obesity worldwide. Further, this study provides scientific evidence for the traditional claim that Ceylon cinnamon has antilipidemic activities.

Lovastatin as Salvage Immunomodulatory Therapy in Patients with Refractory and Relapsed Multipla Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1567-1567 ◽  
Author(s):  
Marek Hus ◽  
Norbert Grzasko ◽  
Dariusz Jawniak ◽  
Marta Szostek ◽  
Anna Dmoszynska
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Light Chain ◽  
Protein Level ◽  
Mevalonate Pathway ◽  
Sinus Bradycardia ◽  
Autologous Transplantation ◽  
M Protein ◽  
Hmg Coa Reductase ◽  
Coa Reductase

Abstract In the recent years the treatment of patients with multiple myeloma (MM) has changed because of the introduction of new agents, mainly thalidomide (THAL) and its derivatives and bortezomib, an inhibitor of the 20S proteasome. Lovastatin (LOV) and other inhibitors of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, have been demonstrated to exibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines including our own experiments. This observation induced us to administer LOV in combination with THAL and dexamethasone (DEX). We report here our preliminary experiences with THAL and LOV therapy in patients with refractory and relapsed MM. We have treated 81 patients with THAL+DEX regimen (TD) or THAL+DEX+LOV regimen (TLD). Patients received drugs orally in 28 day cycles. THAL was given from day 1 to day 28 each cycle and it was started at a initial dose of 100 mg daily increased to 300 mg daily. DEX was administered at a dose of 40 mg daily in days 1–4 each cycle. LOV was administered at a dose of 2 mg/kg in days 1–5 and 8–12 and at a dose of 0.5 mg/kg in days 15–28 each cycle. TLD regimen was administered to 43 patients and TD regimen to 38 patients. Patients characteristics before treatment were as follows: the median age 61.2 years; 61% of patients IgG, 26% IgA, 7% light chain and 6% other; 76% of patients were light chain kappa and 24% lambda; median serum M-protein level was 4.2 g/dl, bone marrow plasma cells 47%, hemoglobin 10.1 g/dl, platelets 197 G/l, beta-2-microglobulin 4.2 mg/ml, albumin 3.9 g/dl and LDH 292 IU. The median follow-up was 29 month. A clinical response, defined as a reduction of M-protein level by 50% or more, was observed in 67.8% of patients in TD group and in 88.0% in TLD group. CR i NCR was observed in 35.0% and 62.7% respectively. In 11 TLD (25.5%.) and 4 TD (10.5%) patients successful stem cell harvest was performed and mean amount of collected CD34+ cells was 8.2*106/kg. Successful autologous transplantation was performed in 8 patients from this group. Overall survival in TLD group (median 23.0 months) was significantly longer than in TD group (median 18.0 months). Similarly event free survival was longer in TLD (median 7.0 months) group than in TD group (4.5 months). We observed significant negative correlation between response and bone marrow infiltration (p=0.008), M-protein level (p=0.0004) and positive correlation between response and albumin level (p=0.005). Short time to reduction of M-protein by 50% was connected with better response. Common side effects as somnolence, fatigue and constipation were observed in about 45% of patients in TLD and TD groups. In 2 TLD and in 3 TD patients we diagnosed deep vein thrombosis. In 2 TLD patients sinus bradycardia was observed. Our results suggest that addition of LOV to THAL and DEX improves response rate in patients with refactory and relapsed MM. Moreover it is possible to harvest stem cells and perform autologous stem cells graft in patients treated with such regimen. A future prospective randomised study is needed to confirm the value of LOV or other HMG-CoA reductase inhibitors in the treatment of MM patients.

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