RESUMO
Spontaneous preterm delivery (SPTD) with gestational age between 28 and 37 complete weeks was reported to have a genetic predisposition in lipids metabolism. This study aimed to investigate the association between the lipid levels and gene polymorphisms of ABCA1 (rs2422493), APOE (rs7412) and HMGCR (rs12916) in Chinese pregnant women with SPTD. A case-control study was conducted at the baseline randomization in 200 SPTD and 178 healthy full term delivery (FTD) women. Maternal blood lipids were detected close to delivery of fetus in SPTD group and in FTD group with gestational age-matched. Cord blood lipids were detected after delivery in two groups. Three genotypes both in maternal and cord blood were determined by real time PCR. The results showed that the levels of total cholesterol (TCHO), triglyceride (TG), high density lipoprotein (HDL), and low-density lipoprotein cholesterol (LDL) in the maternal blood in the SPTD group were significantly lower than those in the FTD group, while the levels of TCHO, HDL, and LDL in the cord blood in the SPTD group were significantly higher than those in the FTD group. In the SPTD subjects, the levels of TG and LDL in the maternal blood were associated with different genotypes of HMGCR gene rs12916 loci. These results indicate that abnormal lipid metabolism may exist in SPTD women and the premature fetus and the HMGCR gene may be a susceptible gene for SPTD.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Apolipoproteínas E/genética , Hidroximetilglutaril-CoA Redutases/genética , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único/fisiologia , Nascimento Prematuro/genética , Transportador 1 de Cassete de Ligação de ATP/fisiologia , Adulto , Apolipoproteínas E/fisiologia , Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Sangue Fetal/química , Predisposição Genética para Doença , Humanos , Hidroximetilglutaril-CoA Redutases/fisiologia , Lipoproteínas HDL/sangue , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Nascimento Prematuro/sangue , Triglicerídeos/sangue , Adulto JovemAssuntos
Colesterol/metabolismo , Lipoproteínas/metabolismo , Acetil-CoA C-Acetiltransferase/antagonistas & inibidores , Acetil-CoA C-Acetiltransferase/fisiologia , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Bile/metabolismo , Transporte Biológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Colesterol na Dieta/farmacocinética , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Modelos Animais de Doenças , Homeostase , Humanos , Hidroximetilglutaril-CoA Redutases/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Hipercolesterolemia/fisiopatologia , Hipolipemiantes/uso terapêutico , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Macrófagos/metabolismoRESUMO
The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme in the biosynthesis of cholesterol and isoprenoids, which are substrates required for post-translational modification of signalling proteins that can potentially regulate various aspects of embryonic development. The HMGCR transcripts are detectable during early embryogenesis in both invertebrates and vertebrates, which suggests a conserved developmental requirement for mevalonate derivatives. Consistently, recent animal and in vitro studies have yielded valuable insights into potential morphogenic parameters that are modulated by HMGCR activity. These developmental end-points include brain and craniofacial morphogenesis, PGC migration and survival, myocardial epithelial migration and fusion, EC migration and survival, and vascular stabilization. By providing a synthesis of these studies, we hope that this review will highlight the need to comprehensively examine the entire suite of developmental processes regulated by HMGCR.
Assuntos
Crescimento/fisiologia , Hidroximetilglutaril-CoA Redutases/fisiologia , Animais , Hidroximetilglutaril-CoA Redutases/genética , Morfogênese/genética , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Prenilação de Proteína/genética , Prenilação de Proteína/fisiologia , Transdução de Sinais/fisiologiaRESUMO
The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs ('statins') directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pneumopatias/tratamento farmacológico , Ácido Mevalônico/metabolismo , Neoplasias/tratamento farmacológico , Alquil e Aril Transferases/antagonistas & inibidores , Animais , Farnesiltranstransferase/antagonistas & inibidores , Humanos , Hidroximetilglutaril-CoA Redutases/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Proteínas rho de Ligação ao GTP/fisiologia , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/fisiologiaRESUMO
Hydroxymethylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme of mevalonate pathway, has been involved in the tumorigenesis of several tumor types. Our previous study has showed that statin, the inhibitor of HMGCR, inhibited the tumorigenecity of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. However, the function of HMGCR in the carcinogenesis of ESCC cells remains unknown. In this study, we have observed the up-regulation of HMGCR in ESCC tissues compared with the paired normal tissues. Over-expression of HMGCR in ESCC cells promoted cell growth and migration, while knockdown of the expression of HMGCR inhibited the growth, migration and colony formation of ESCC cells in vitro and in vivo. Furthermore, we found that oncogene Myc positively regulated the expression of HMGCR. Taken together, our study revealed the pivotal function of HMGCR and mevalonate pathway in the progression of ESCC and supported the clinical application of statin.
Assuntos
Carcinoma de Células Escamosas/etiologia , Neoplasias Esofágicas/etiologia , Genes myc/fisiologia , Hidroximetilglutaril-CoA Redutases/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Carcinoma de Células Escamosas do Esôfago , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Humanos , Ácido Mevalônico/metabolismoRESUMO
The enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzes the conversion of HMG-Co-A into mevalonate. This step is the limiting point for the synthesis of cholesterol in mammals and ergosterol in fungi. We describe in this article the genome organization of HMGR coding genes and those deduced from different fungi, recount the evidence showing statins as HMGR inhibitors for ergosterol synthesis and its effect in yeast viability, and propose fungal HMGR (HMGRf) as a model to study the use of pharmaceutical compounds to inhibit cholesterol and ergosterol synthesis. Bibliographical search and bioinformatic analyses were performed and discussed. HMGRfs belong to the class I with a high homology in the catalytic region. The sterol biosynthetic pathway in humans and fungi share many enzymes in the initial steps (such as the HMGR enzyme), but in the last steps enzymes are different rendering the two final products: cholesterol in mammals and ergosterol in fungi. With regards to inhibitors such as statins and other compounds, these affect also fungal viability. Since HMGR from Schizosaccharomyces pombe and Ustilago maydis are very similar to the human HMGR in the catalytic regions, we propose that fungal enzymes can be used to test inhibitors for a potential use in humans. We consider that HMGRf is a good therapeutic target to design and test new antifungal compounds. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012).
Assuntos
Antifúngicos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas Fúngicas/fisiologia , Fungos/enzimologia , Hidroximetilglutaril-CoA Redutases/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Terapia de Alvo Molecular , Animais , Antifúngicos/uso terapêutico , Candida/enzimologia , Colesterol/biossíntese , Cristalografia por Raios X , Ergosterol/biossíntese , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/genética , Fungos/efeitos dos fármacos , Genes Fúngicos , Humanos , Hidroximetilglutaril-CoA Redutases/química , Hidroximetilglutaril-CoA Redutases/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Micoses/tratamento farmacológico , Micoses/microbiologia , NADP/metabolismo , Roedores/metabolismo , Schizosaccharomyces/enzimologia , Especificidade da Espécie , Ustilago/enzimologiaRESUMO
Cholesterol homeostasis is among the most intensely regulated processes in biology. Since its isolation from gallstones at the time of the French Revolution, cholesterol has been extensively studied. Insufficient or excessive cellular cholesterol results in pathological processes including atherosclerosis and metabolic syndrome. Mammalian cells obtain cholesterol from the circulation in the form of plasma lipoproteins or intracellularly, through the synthesis of cholesterol from acetyl coenzyme A (acetyl-CoA). This process is tightly regulated at multiple levels. In this review, we provide an overview of the multiple mechanisms by which cellular cholesterol metabolism is regulated. We also discuss the recent advances in the post-transcriptional regulation of cholesterol homeostasis, including the role of small non-coding RNAs (microRNAs). These novel findings may open new avenues for the treatment of dyslipidemias and cardiovascular diseases.
Assuntos
Colesterol/metabolismo , Homeostase , Animais , Transporte Biológico , Doenças Cardiovasculares/etiologia , Humanos , Hidroximetilglutaril-CoA Redutases/fisiologia , MicroRNAs/fisiologiaRESUMO
Recent studies support the notion that statins, widely prescribed cholesterol-lowering agents, may target key elements in the immunological cascade leading to inflammation and tissue damage in the pathogenesis of multiple sclerosis (MS). Compelling experimental and observational clinical studies highlighted the possibility that statins may also exert immunomodulatory synergy with approved MS drugs, resulting in several randomized clinical trials testing statins in combination with interferon-beta (IFN-ß). Some data, however, suggest that this particular combination may not be clinically beneficial, and might actually have a negative effect on the disease course in some patients with MS. In this regard, a small North American trial indicated that atorvastatin administered in combination with IFN-ß may increase disease activity in relapsing-remitting MS. Although other trials did not confirm this finding, the enthusiasm for studies with statins dwindled. This review aims to provide a comprehensive overview of the completed clinical trials and reports of the interim analyses evaluating the combination of IFN-ß and statins in MS. Moreover, we try to address the evident question whether usage of this combination routinely requires caution, since the number of IFN-ß-treated MS patients receiving statins for lowering of cholesterol is expected to grow.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Ensaios Clínicos como Assunto , Interações Medicamentosas , Quimioterapia Combinada , Humanos , Hidroximetilglutaril-CoA Redutases/fisiologia , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Eyestalk ablation (ESA) increases crustacean production of methyl farnesoate (MF), a juvenile hormone-like compound, but the biochemical steps involved are not completely understood. We measured the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) and farnesoic acid O-methyl transferase (FAOMeT), an early step and the last step in MF synthesis. ESA elevated hemolymph levels of MF in male lobsters. Enzyme activity suggested that increased MF production on day one was due largely to elevated HMGR activity while changes in FAOMeT activity closely paralleled changes in MF levels on day 14. Transcript levels for HMGR and FAOMeT changed little on day one, but both increased substantially on day 14. We treated ESA males with a partially purified mandibular organ-inhibiting hormone (MOIH) and observed a significant decline in MF levels, FAOMeT activity, and FAOMeT-mRNA levels after 5h. However, no effect was observed on HMGR activity or its mRNA indicating that they must be regulated by a separate sinus gland peptide. We confirmed that lobster HMGR was not a phosphoprotein and was not regulated by reversible phosphorylation, an important mechanism for regulating other HMGRs. Nevertheless, molecular modeling indicated that the catalytic mechanisms of lobster and mammalian HMGR were similar.
Assuntos
Ácidos Graxos Insaturados/biossíntese , Hidroximetilglutaril-CoA Redutases/fisiologia , Mandíbula/metabolismo , Metiltransferases/fisiologia , Nephropidae/metabolismo , Sequência de Aminoácidos , Animais , Enucleação Ocular , Regulação Enzimológica da Expressão Gênica , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Nephropidae/enzimologia , Nephropidae/genética , Fosforilação , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Homologia de Sequência de AminoácidosRESUMO
Analogs of vitamin E (tocols) are under development as radioprophylactic agents because of their high efficacy and lack of toxicity. Gamma-tocotrienol (GT3) is of particular interest because, in addition to being an antioxidant, it also inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and accumulates to greater extent in endothelial cells than other tocols. We addressed in vivo whether HMG-CoA reductase inhibition contributes to the radioprotection conferred by GT3. Groups of mice were treated with vehicle, mevalonate (the product of the reaction catalyzed by HMG-CoA reductase), GT3 alone or GT3 in combination with mevalonate. Lethality and standard parameters of injury to the hematopoietic, intestinal and vascular/endothelial systems were assessed after exposure to total-body irradiation. GT3 improved postirradiation survival and decreased radiation-induced vascular oxidative stress, an effect that was reversible by mevalonate. GT3 also enhanced hematopoietic recovery, reduced intestinal radiation injury, and accelerated the recovery of soluble markers of endothelial function. These parameters were not reversed by mevalonate co-administration. Our data confirm GT3's radioprophylactic properties against hematopoietic injury and, for the first time, demonstrate benefits in terms of protection against gastrointestinal and vascular injury. The radioprotective efficacy of GT3 against vascular injury is related to its properties as an HMG-CoA reductase inhibitor.
Assuntos
Cromanos/farmacologia , Hidroximetilglutaril-CoA Redutases/fisiologia , Intestinos/efeitos da radiação , Estresse Oxidativo/efeitos dos fármacos , Protetores contra Radiação/farmacologia , Vitamina E/análogos & derivados , Irradiação Corporal Total , Animais , Masculino , Camundongos , Vitamina E/farmacologiaRESUMO
OBJECTIVE: Integrin-mediated cell adhesion to type I fibrillar collagen regulates gene and protein expression, whereas little is known of its effect on lipid metabolism. In the present study, we examined the effect of type I fibrillar collagen on cholesterol biosynthesis in human aortic smooth muscle cells (SMCs). METHODS AND RESULTS: SMCs were cultured on either fibrillar or monomer collagen for 48 hours and [(14)C]-acetate incorporation into cholesterol was evaluated. Fibrillar collagen reduced by 72.9+/-2.6% cholesterol biosynthesis without affecting cellular cholesterol levels. Fibrillar collagen also reduced 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) promoter activity (-72.6+/-7.3%), mRNA (-58.7+/-6.4%), protein levels (-35.5+/-8.5%), and enzyme activity (-37.7+/-2.2%). Intracellular levels of the active form of sterol regulatory element binding proteins (SREBP) 1a was decreased by 60.7+/-21.7% in SMCs cultured on fibrillar collagen, whereas SREBP2 was not significantly affected (+12.1+/-7.1%). The overexpression of the active form of SREBP1a rescued the downregulation of fibrillar collagen on HMG-CoA reductase levels. Blocking antibody to alpha2 integrin partially reversed the downregulation of HMG-CoA reductase mRNA expression. Finally, fibrillar collagen led to an intracellular accumulation of unprenylated Ras. CONCLUSIONS: Our study demonstrated that alpha2 beta 1 integrin interaction with fibrillar collagen affected the expression of HMG-CoA reductase, which led to the inhibition of cholesterol biosynthesis in human SMCs.
Assuntos
Colesterol/biossíntese , Colágenos Fibrilares/fisiologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Aorta Torácica/metabolismo , Adesão Celular , Células Cultivadas , Regulação Enzimológica da Expressão Gênica , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/fisiologia , Integrina alfa2beta1/fisiologia , Músculo Liso Vascular/citologia , Prenilação de Proteína , RNA Mensageiro/análise , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteínas ras/metabolismoRESUMO
In many species, the germ cells, precursors of sperm and egg, migrate during embryogenesis. The signals that regulate this migration are thus essential for fertility. In flies, lipid signals have been shown to affect germ cell guidance. In particular, the synthesis of geranylgeranyl pyrophosphate through the 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (Hmgcr) pathway is critical for attracting germ cells to their target tissue. In a genetic analysis of signaling pathways known to affect cell migration of other migratory cells, we failed to find a role for the Hedgehog (Hh) pathway in germ cell migration. However, previous reports had implicated Hh as a germ cell attractant in flies and suggested that Hh signaling is enhanced through the action of the Hmgcr pathway. We therefore repeated several critical experiments and carried out further experiments to test specifically whether Hh is a germ cell attractant in flies. In contrast to previously reported findings and consistent with findings in zebrafish our data do not support the notion that Hh has a direct role in the guidance of migrating germ cells in flies.
Assuntos
Movimento Celular/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila/fisiologia , Células Germinativas/fisiologia , Proteínas Hedgehog/fisiologia , Animais , Drosophila/embriologia , Proteínas de Drosophila/genética , Proteínas Hedgehog/genética , Hidroximetilglutaril-CoA Redutases/fisiologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Mutação , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: HMGCR(3-Hydroxy-3-methylglutaryl coenzyme A reductase), the direct target of statin inhibition, undergoes alternative splicing of exon 13, which encodes part of the statin-binding domain of the enzyme. We hypothesized that HMGCR alternative splicing might be related to the interindividual variation in plasma low-density lipoprotein cholesterol response to statin treatment. METHODS AND RESULTS: We measured mRNA expression of both the full-length and the alternatively spliced HMGCR transcript lacking exon 13 (HMGCRv_1) in 170 simvastatin-incubated immortalized lymphocyte cell lines derived from participants in the Cholesterol and Pharmacogenetics (CAP) study who were treated with simvastatin 40 mg/d for 6 weeks. Greater upregulation of HMGCRv_1 in vitro was significantly correlated (PAssuntos
Processamento Alternativo/fisiologia
, LDL-Colesterol/efeitos dos fármacos
, Hidroximetilglutaril-CoA Redutases/genética
, Sinvastatina/farmacologia
, Adulto
, Apolipoproteínas B/sangue
, População Negra
, Linhagem Celular
, LDL-Colesterol/sangue
, Feminino
, Humanos
, Hidroximetilglutaril-CoA Redutases/fisiologia
, Linfócitos/citologia
, Linfócitos/efeitos dos fármacos
, Masculino
, Cooperação do Paciente
, Polimorfismo de Nucleotídeo Único
, RNA Mensageiro/análise
, Sinvastatina/administração & dosagem
, Triglicerídeos/sangue
, Regulação para Cima
, População Branca
RESUMO
Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which initiates the syntheses of cholesterol and isoprenoid lipids that are needed to provide amyloid peptides for the amyloid cascade. This cascade is believed to induce sporadic or late-onset Alzheimer's disease, which accounts for 90 - 95% of Alzheimer's disease sufferers. Cholesterol is also the prime driver of cerebrovascular disease that (along with amyloid peptides) increasingly appears to be linked to the cognitive deterioration of Alzheimer's disease. Cholesterol is needed to make the lipid rafts that are the platforms for isoprenoid-dependent assembly and activation of raftophilic beta- and gamma-secretases that work in tandem to excise dangerous 40 and 42 amino acid amyloid-beta (Abeta) fragments from amyloid precursor protein, the transmembrane amyloid precursor glycoprotein. When they are excessively produced and can no longer be effectively destroyed or otherwise cleared from the hypoperfused ageing brain, the Abeta42 fragments released from the active synaptic terminals of normally busy neurons (and from stressed neurons unsuccessfully trying to proliferate and producing disruptive tangles of hyperphosphorylated tau-proteins) aggregate into neuritic plaques, which activate glial cells. The pro-inflammatory cytokines and growth factors from the glial cells further damage and kill neurons. As statins strike at several parts of the Alzheimer's disease mechanism (such as the infliction of cholesterol-dependent cerebrovascular damage) by inhibiting HMG-CoA reductase, their long-term use (starting as early as possible during Alzheimer's disease development) should slow or even prevent the progression of Alzheimer's disease. Indeed, there is some evidence of a significantly reduced incidence of Alzheimer's disease among people who have been using statins to reduce hypercholesterolaemia and its cardiovascular effects. To be certain of this, there must be more multi-year trials to specifically assess the effects of statins on sporadic Alzheimer's disease.
Assuntos
Doença de Alzheimer/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Compartimento Celular , Células Cultivadas/efeitos dos fármacos , Colesterol/metabolismo , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Ativação Enzimática , Humanos , Hidroximetilglutaril-CoA Redutases/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Arteriosclerose Intracraniana/metabolismo , Arteriosclerose Intracraniana/prevenção & controle , Lipídeos de Membrana/metabolismo , Microdomínios da Membrana/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/fisiologia , Neurônios/metabolismo , Processamento de Proteína Pós-TraducionalAssuntos
Cardiomiopatias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/prevenção & controle , Ensaios Clínicos como Assunto , Coenzimas , Humanos , Hidroximetilglutaril-CoA Redutases/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/classificação , Miocárdio Atordoado/tratamento farmacológico , Miocárdio Atordoado/etiologia , Miocárdio/enzimologia , Óleos , Pravastatina/efeitos adversos , Pravastatina/uso terapêutico , Sinvastatina/efeitos adversos , Sinvastatina/uso terapêutico , Solubilidade , Ubiquinona/análogos & derivados , Ubiquinona/fisiologia , ÁguaRESUMO
BACKGROUND AND PURPOSE: Atorvastatin is an inhibitor of the enzyme 3-hydroxyl-3-methylglutaryl coenzyme A reductase used to prevent coronary heart disease. We have studied the analgesic effect of atorvastatin in inflammatory models in which a sequential release of mediators (bradykinin, (BK), tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and the chemokine, KC/CXCL) links the stimulus with release of directly acting hypernociceptive mediators such as prostaglandin E(2) (PGE(2)). EXPERIMENTAL APPROACH: The effects of orally administered atorvastatin on inflammatory mechanical hypernociception in mouse paws were evaluated with an electronic pressure-meter. Cytokines and PGE(2) were measured by ELISA and RIA. KEY RESULTS: Treatment with atorvastatin for 3 days dose-dependently reduced hypernociception induced by lipopolysaccharide (LPS) or that following antigen challenge in sensitized animals. Atorvastatin pre-treatment reduced hypernociception induced by bradykinin and cytokines (TNF-alpha, IL-1beta and KC), and the release of IL-1beta and PGE(2) in paw skin, induced by lipopolysaccharide. The antinociceptive effect of atorvastatin on LPS-induced hypernociception was prevented by mevalonate co-treatment without affecting serum cholesterol levels. Hypernociception induced by PGE(2) was inhibited by atorvastatin, suggesting intracellular antinociceptive mechanisms for atorvastatin. The antinociceptive effect of atorvastatin upon LPS- or PGE(2)-induced hypernociception was prevented by non-selective inhibitors of nitric oxide synthase (NOS) but not by selective inhibition of inducible NOS or in mice lacking this enzyme. CONCLUSIONS AND IMPLICATIONS: Antinociceptive effects of atorvastatin depend on inhibition of cytokines and prostanoid production and on stimulation of NO production by constitutive NOS. Our study suggests that statins may constitute a novel class of analgesic drugs.
Assuntos
Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Inflamação/complicações , Pirróis/farmacologia , Animais , Atorvastatina , Bradicinina/farmacologia , Colesterol/sangue , Citocinas/farmacologia , Dinoprostona/metabolismo , Inibidores Enzimáticos/farmacologia , Hidroximetilglutaril-CoA Redutases/fisiologia , Hiperalgesia/prevenção & controle , Interleucina-1/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Óxido Nítrico Sintase/antagonistas & inibidores , Medição da Dor/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismoRESUMO
Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.
Assuntos
Apoptose/efeitos dos fármacos , Lovastatina/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/patologia , Animais , Apoptose/fisiologia , Antígenos CD36/biossíntese , Células Cultivadas , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Células Jurkat , Lovastatina/administração & dosagem , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Lisofosfolipídeos/antagonistas & inibidores , Lisofosfolipídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/citologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/enzimologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Monócitos/citologia , Fagocitose/fisiologia , Prenilação de Proteína/efeitos dos fármacos , Prenilação de Proteína/fisiologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Both angiotensin receptor antagonists and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to attenuate cardiomyocyte hypertrophy after myocardial infarction. Whether combination treatment may be superior to either drug alone on cardiomyocyte hypertrophy remains unclear. After ligation of the left anterior descending artery, rats were randomized to both, one, or neither of the angiotensin receptor antagonists olmesartan (0.01, 0.1, 1, and 2 mg.kg-1.day-1) and HMG-CoA reductase inhibitor pravastatin (5 mg.kg-1.day-1) for 4 wk. Each drug, when given alone, decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone when compared with vehicles. However, compared with either drug alone, combined olmesartan and pravastatin prevent cardiomyocyte hypertrophy to a larger extent, which was further confirmed by downregulation of the left ventricular atrial natriuretic peptide mRNA. The myocardial endothelin-1 levels at the border zone were 6.5-fold higher (P<0.0001) in the vehicle group compared with the sham group, which can be inhibited after pravastatin administration. Combination treatment significantly attenuated cardiomyocyte hypertrophy in a dose-dependent manner, although tissue endothelin-1 levels remained stable in combination groups of different olmesartan doses. Measurements of the arrhythmic score mirrored those of cardiomyocyte hypertrophy. Dual therapy with pravastatin and olmesartan, which produced an additive reduction in cardiomyocyte hypertrophy and cardiac fibrosis after myocardial infarction through different mechanisms, decreases the propensity of the heart to arrhythmogenesis. Pravastatin administration provided favorable ventricular remodeling, probably through decreased tissue endothelin-1 level. In contrast, olmesartan-related attenuated cardiomyocyte hypertrophy is independent of endothelin-1 pathway.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Imidazóis/farmacologia , Infarto do Miocárdio/fisiopatologia , Pravastatina/farmacologia , Tetrazóis/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Endotelina-1/genética , Endotelina-1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Hidroximetilglutaril-CoA Redutases/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Imidazóis/uso terapêutico , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Pravastatina/uso terapêutico , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/fisiologia , Tetrazóis/uso terapêutico , Remodelação Ventricular/fisiologiaRESUMO
Drosophila HMGCoA reductase (hmgcr) catalyzes the biosynthesis of a mevalonate precursor for isoprenoids and has been implicated in the production of a signal by the somatic gonadal precursor cells (SGPs) that attracts migrating germ cells. Here, we show that hmgcr functions in the hedgehog (hh) signaling pathway. When hmgcr activity is reduced, high levels of Hh accumulate in hh-expressing cells in each parasegment, while the adjacent "Hh-receiving" cells cannot sustain wg expression and fail to relocalize the Smoothened (Smo) receptor. Conversely, ectopic Hmgcr upregulates Hh signaling when it is produced in hh-expressing cells, but has no effect when produced in the receiving cells. These findings suggest that Hmgcr might orchestrate germ cell migration by promoting the release and/or transport of Hh from the SGPs. Consistent with this model, there are substantial germ cell migration defects in trans combinations between hmgcr and mutations in different components of the hh pathway.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Hidroximetilglutaril-CoA Redutases/fisiologia , Transdução de Sinais/fisiologia , Animais , Movimento Celular/fisiologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/embriologia , Proteínas Hedgehog , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Mutação , Fenótipo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened , Asas de Animais/embriologia , Asas de Animais/fisiologia , Proteína Wnt1RESUMO
RATIONALE: A growing literature indicates that hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins) modulate proinflammatory cellular signaling and functions. No studies to date, however, have addressed whether statins modulate pulmonary inflammation triggered by aerogenic stimuli or whether they affect host defense. OBJECTIVES: To test whether lovastatin modulates LPS-induced pulmonary inflammation and antibacterial host defense. METHODS: To address these questions, and to confirm any effect of statins as dependent on inhibition of hydroxy-methylglutaryl coenzyme A reductase, we treated C57Bl/6 mice with three oral doses of 10 mg/kg lovastatin (or vehicle) and three intraperitoneal doses of 10 mg/kg mevalonic acid (or saline), and then exposed them to the following: (1) aerosolized LPS, (2) intratracheal keratinocyte-derived chemokine (KC), or (3) intratracheal Klebsiella pneumoniae. MEASUREMENTS AND MAIN RESULTS: LPS- and KC-induced airspace neutrophils were reduced by lovastatin, an effect that was blocked by mevalonic acid cotreatment. Lovastatin was also associated with reduced parenchymal myeloperoxidase and microvascular permeability, and altered airspace and serum cytokines after LPS. Native pulmonary clearance of K. pneumoniae was inhibited by lovastatin and extrapulmonary dissemination was enhanced, both reversibly with mevalonic acid. Ex vivo studies of neutrophils isolated from lovastatin-treated mice confirmed inhibitory effects on Rac activation, actin polymerization, chemotaxis, and bacterial killing. CONCLUSION: Lovastatin attenuates pulmonary inflammation induced by aerosolized LPS and impairs host defense.