RESUMO
AIMS: Increased lipid peroxidation occurs in many conditions associated with inflammation. Because lipid peroxidation produces lipid aldehydes that can induce inflammatory responses through unknown mechanisms, elucidating these mechanisms may lead to development of better treatments for inflammatory diseases. We recently demonstrated that exposure of cultured cells to lipid aldehydes such as isolevuglandins (IsoLG) results in the modification of phosphatidylethanolamine (PE). We therefore sought to determine (i) whether PE modification by isolevuglandins (IsoLG-PE) occurred in vivo, (ii) whether IsoLG-PE stimulated the inflammatory responses of macrophages, and (iii) the identity of receptors mediating the inflammatory effects of IsoLG-PE. RESULTS: IsoLG-PE levels were elevated in plasma of patients with familial hypercholesterolemia and in the livers of mice fed a high-fat diet to induce obesity and hepatosteatosis. IsoLG-PE potently stimulated nuclear factor kappa B (NFκB) activation and expression of inflammatory cytokines in macrophages. The effects of IsoLG-PE were blocked by the soluble form of the receptor for advanced glycation endproducts (sRAGE) and by RAGE antagonists. Furthermore, macrophages derived from the bone marrow of Ager null mice failed to express inflammatory cytokines in response to IsoLG-PE to the same extent as macrophages from wild-type mice. INNOVATION: These studies are the first to identify IsoLG-PE as a mediator of macrophage activation and a specific receptor, RAGE, which mediates its biological effects. CONCLUSION: PE modification by IsoLG forms RAGE ligands that activate macrophages, so that the increased IsoLG-PE generated by high circulating cholesterol levels or high-fat diet may play a role in the inflammation associated with these conditions.
Assuntos
Aldeídos/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Fosfatidiletanolaminas/metabolismo , Prostaglandinas E/química , Pirrolidinas/química , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Humanos , Lipídeos/química , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Fosfatidiletanolaminas/química , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidoresRESUMO
Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide, 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to Western diet (WD) at 2.2% by weight, and fed to LDL receptor-null (LDLR(-/-)) mice at 45 mg/kg/day 6F. After 13 weeks, the percent of the aorta with lesions was 4.1 ± 4%, 3.3 ± 2.4%, and 1.9 ± 1.4% for WD, WD + EV, and WD + 6F, respectively (WD + 6F vs. WD, P = 0.0134; WD + 6F vs. WD + EV, P = 0.0386; WD + EV vs. WD, not significant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD + 6F mice; P < 0.0295. HDL cholesterol and paroxonase-1 activity (PON) were higher in WD + 6F mice (P = 0.0055 and P = 0.0254, respectively), but not in WD + EV mice. Plasma SAA, total cholesterol, triglycerides, LPA, and 15-hydroxyeicosatetraenoic acid (HETE) levels positively correlated with lesions (P < 0.0001); HDL cholesterol and PON were inversely correlated (P < 0.0001). After feeding WD + 6F: i) intact 6F was detected in small intestine (but not in plasma); ii) small intestine LPA was decreased compared with WD + EV (P < 0.0469); and iii) small intestine LPA 18:2 positively correlated with the percent of the aorta with lesions (P < 0.0179). These data suggest that 6F acts in the small intestine and provides a novel approach to oral apoA-I mimetic therapy.
Assuntos
Apolipoproteína A-I/química , Peptídeos/química , Peptídeos/uso terapêutico , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Colesterol/sangue , Feminino , Ácidos Hidroxieicosatetraenoicos/sangue , Intestino Delgado/metabolismo , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Lisofosfolipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos/genética , Peptídeos/metabolismo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Triglicerídeos/sangueRESUMO
Oxidized phospholipids are found in the vasculature of animal models of atherosclerosis, in human atherosclerotic lesions, and in other inflammatory diseases. Oxidized phospholipids cause vascular and nonvascular cells to initiate an inflammatory reaction. Metabolites of arachidonic acid, such as 12-hydroxyeicosatetraenoic acid, can mimic some of the inflammatory properties of oxidized phospholipids. In vitro and in vivo normal high-density lipoprotein (HDL), normal apolipoprotein A-I, and apolipoprotein A-I mimetic peptides, each likely acting in a different manner, prevent the inflammatory reaction characteristic of atherosclerosis, and this is associated with decreased levels of oxidized lipids in tissues and cells. HDL from animal models of atherosclerosis or from humans with atherosclerosis or from humans or animals with other chronic inflammatory diseases does not prevent the inflammatory reaction characteristic of atherosclerosis and may even enhance the inflammatory reaction. In mice and perhaps humans, ≈30% of the steady-state plasma HDL-cholesterol pool is derived from the small intestine. The metabolism of phospholipids by gut bacteria has been recently implicated in atherosclerosis in both mice and humans. Studies with apolipoprotein A-I mimetic peptides suggest that the small intestine is a major tissue regulating systemic inflammation in mouse models of atherosclerosis and may be important for determining the functionality of HDL.
Assuntos
Anti-Inflamatórios/farmacologia , Aterosclerose/prevenção & controle , Vasos Sanguíneos/metabolismo , Inflamação/prevenção & controle , Intestino Delgado/efeitos dos fármacos , Lipoproteínas HDL/metabolismo , Peptídeos/farmacologia , Fosfolipídeos/metabolismo , Animais , Ácido Araquidônico/metabolismo , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/patologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Intestino Delgado/metabolismo , Lipoproteínas LDL/metabolismo , OxirreduçãoRESUMO
The liver X receptor (LXR) signaling pathway is an important modulator of atherosclerosis, but the relative importance of the two LXRs in atheroprotection is incompletely understood. We show here that LXRα, the dominant LXR isotype expressed in liver, plays a particularly important role in whole-body sterol homeostasis. In the context of the ApoE(-/-) background, deletion of LXRα, but not LXRß, led to prominent increases in atherosclerosis and peripheral cholesterol accumulation. However, combined loss of LXRα and LXRß on the ApoE(-/-) background led to an even more severe cholesterol accumulation phenotype compared to LXRα(-/-)ApoE(-/-) mice, indicating that LXRß does contribute to reverse cholesterol transport (RCT) but that this contribution is quantitatively less important than that of LXRα. Unexpectedly, macrophages did not appear to underlie the differential phenotype of LXRα(-/-)ApoE(-/-) and LXRß(-/-)ApoE(-/-) mice, as in vitro assays revealed no difference in the efficiency of cholesterol efflux from isolated macrophages. By contrast, in vivo assays of RCT using exogenously labeled macrophages revealed a marked defect in fecal sterol efflux in LXRα(-/-)ApoE(-/-) mice. Mechanistically, this defect was linked to a specific requirement for LXRα(-/-) in the expression of hepatic LXR target genes involved in sterol transport and metabolism. These studies reveal a previously unrecognized requirement for hepatic LXRα for optimal reverse cholesterol transport in mice.
Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Colesterol/metabolismo , Receptores Nucleares Órfãos/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Fígado/metabolismo , Receptores X do Fígado , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , FenótipoRESUMO
We examined whether reduced levels of Apolipoprotein A-I (apoA-I) in ovarian cancer patients are causal in ovarian cancer in a mouse model. Mice expressing a human apoA-I transgene had (i) increased survival (P < 0.0001) and (ii) decreased tumor development (P < 0.01), when compared with littermates, following injection of mouse ovarian epithelial papillary serous adenocarcinoma cells (ID-8 cells). ApoA-I mimetic peptides reduced viability and proliferation of ID8 cells and cis-platinum-resistant human ovarian cancer cells, and decreased ID-8 cell-mediated tumor burden in C57BL/6J mice when administered subcutaneously or orally. Serum levels of lysophosphatidic acid, a well-characterized modulator of tumor cell proliferation, were significantly reduced (>50% compared with control mice, P < 0.05) in mice that received apoA-I mimetic peptides (administered either subcutaneously or orally), suggesting that binding and removal of lysophosphatidic acid is a potential mechanism for the inhibition of tumor development by apoA-I mimetic peptides, which may serve as a previously unexplored class of anticancer agents.
Assuntos
Apolipoproteína A-I/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Peptídeos/uso terapêutico , Lesões Pré-Cancerosas/tratamento farmacológico , Animais , Apolipoproteína A-I/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Feminino , Humanos , Injeções , Lisofosfolipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transplante de Neoplasias/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Peptídeos/farmacologia , Lesões Pré-Cancerosas/patologia , Análise de Sobrevida , Carga Tumoral , ÁguaRESUMO
To determine in vivo if L-4F differentially alters plasma levels of oxidized fatty acids resulting in more anti-inflammatory HDL. Injecting L-4F into apoE null mice resulted in a significant reduction in plasma levels of 15-HETE, 5-HETE, 13-HODE and 9-HODE. In contrast, plasma levels of 20-HETE were not reduced and plasma levels of 14,15-EET, which are derived from the cytochrome P450 pathway, were elevated after injection of L-4F. Injection of 13(S)-HPODE into wild-type C57BL/6J mice caused an increase in plasma levels of 13-HODE and 9-HODE and was accompanied by a significant loss in the anti-inflammatory properties of HDL. The response of atherosclerosis resistant C3H/HeJ mice to injection of 13(S)-HPODE was similar but much more blunted. Injection of L-4F at a site different from that at which the 13(S)-HPODE was injected resulted in significantly lower plasma levels of 13-HODE and 9-HODE and significantly less loss of HDL anti-inflammatory properties in both strains. i) L-4F differentially alters plasma levels of oxidized fatty acids in vivo. ii) The resistance of the C3H/HeJ strain to atherosclerosis may in part be mediated by a reduced reaction of this strain to these potent lipid oxidants.
Assuntos
Anti-Inflamatórios/administração & dosagem , Ácidos Graxos/sangue , Lipoproteínas HDL/sangue , Peptídeos/administração & dosagem , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/sangue , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/prevenção & controle , Cromatografia Líquida , Ensaio de Imunoadsorção Enzimática , Feminino , Ácidos Hidroxieicosatetraenoicos/sangue , Injeções Subcutâneas , Ácidos Linoleicos/administração & dosagem , Ácidos Linoleicos/sangue , Ácidos Linoleicos Conjugados/sangue , Peróxidos Lipídicos/administração & dosagem , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , Especificidade da Espécie , Espectrometria de Massas em Tandem , Fatores de Tempo , Regulação para CimaRESUMO
HDL mimetics have been constructed from a number of peptides and proteins with varying structures, all of which bind lipids found in HDL. HDL mimetics containing a peptide or protein have been constructed with as few as 4 and as many as 243 amino acid residues. Some HDL mimetics have been constructed with lipid but without a peptide or protein component. Some HDL mimetics promote cholesterol efflux, some have been shown to have a remarkable ability to bind oxidized lipids compared to human apolipoprotein A-I (apoA-I). Many of these peptides have been shown to have antiinflammatory properties. Based on studies in a number of animal models and in early human clinical trials, HDL mimetics appear to have promise as diagnostic and therapeutic agents.
Assuntos
Anti-Inflamatórios/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Hipolipemiantes/farmacologia , Lipoproteínas HDL/metabolismo , Mimetismo Molecular , Peptídeos/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Apolipoproteína A-I/metabolismo , Doenças Cardiovasculares/metabolismo , Colesterol/metabolismo , Humanos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/química , Hipolipemiantes/metabolismo , Lipoproteínas HDL/química , Oxirredução , Peptídeos/administração & dosagem , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Relação Estrutura-AtividadeAssuntos
Reação de Fase Aguda/metabolismo , HDL-Colesterol/metabolismo , Diabetes Mellitus/metabolismo , Animais , Animais Endogâmicos , Apolipoproteína A-I/metabolismo , Biomarcadores , HDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Doença das Coronárias/metabolismo , Hemoglobinas/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Hanseníase/metabolismo , Peroxidação de Lipídeos , Lúpus Eritematoso Sistêmico/metabolismo , Síndrome Metabólica/metabolismo , Camundongos , Obesidade/metabolismo , Estresse Oxidativo , Valor Preditivo dos Testes , Coelhos , Medição de Risco , Fatores de RiscoRESUMO
4F is an anti-inflammatory, apolipoprotein A-I (apoA-I)-mimetic peptide that is active in vivo at nanomolar concentrations in the presence of a large molar excess of apoA-I. Physiologic concentrations ( approximately 35 microM) of human apoA-I did not inhibit the production of LDL-induced monocyte chemotactic activity by human aortic endothelial cell cultures, but adding nanomolar concentrations of 4F in the presence of approximately 35 microM apoA-I significantly reduced this inflammatory response. We analyzed lipid binding by surface plasmon resonance. The anti-inflammatory 4F peptide bound oxidized lipids with much higher affinity than did apoA-I. Initially, we examined the binding of PAPC (1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine) and observed that its oxidized products bound 4F with an affinity that was approximately 4-6 orders of magnitude higher than that of apoA-I. This high binding affinity was confirmed in studies with defined lipids and phospholipids. 3F-2 and 3F(14) are also amphipathic alpha-helical octadecapeptides, but 3F-2 inhibits atherosclerosis in mice and 3F(14) does not. Like 4F, 3F-2 also bound oxidized phospholipids with very high affinity, whereas 3F(14) resembled apoA-I. The extraordinary ability of 4F to bind pro-inflammatory oxidized lipids probably accounts for its remarkable anti-inflammatory properties.
Assuntos
Apolipoproteína A-I/metabolismo , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos/fisiologia , Mimetismo Molecular/fisiologia , Peptídeos/metabolismo , Sequência de Aminoácidos , Anti-Inflamatórios não Esteroides/metabolismo , Apolipoproteína A-I/fisiologia , Células Cultivadas , Humanos , Mediadores da Inflamação/fisiologia , Dados de Sequência Molecular , Fosfolipídeos/metabolismo , Ligação Proteica/fisiologiaRESUMO
The mouse has proven to be an excellent model for testing apolipoprotein mimetic peptides as agents to treat a variety of vascular inflammatory conditions including atherosclerosis, cognitive dysfunction associated with arteriole inflammation, chronic rejection of transplanted hearts, and scleroderma. The mechanism of action appears to relate to the ability of these peptides to preferentially bind pro-inflammatory oxidized lipids and is independent of the chirality of the peptides since peptides synthesized from either D- or L-amino acids appear to be equally effective.
Assuntos
Apolipoproteína A-I/uso terapêutico , Aterosclerose/prevenção & controle , Materiais Biomiméticos/uso terapêutico , Modelos Animais de Doenças , Peptídeos/uso terapêutico , Animais , Apolipoproteína A-I/metabolismo , Aterosclerose/metabolismo , Materiais Biomiméticos/metabolismo , Humanos , Camundongos , Peptídeos/metabolismo , Ligação Proteica/fisiologiaRESUMO
Rabbits on a 1% cholesterol diet received injections of vehicle with or without D-4F or L-4F. After 1 month, the percent of aorta with atherosclerotic lesions was 24 +/- 15% (vehicle), 10 +/- 6% (D-4F) (P < 0.01 vs. vehicle), and 13 +/- 9% (L-4F) (P < 0.05 vs. vehicle). Inflammatory indexes for HDL and LDL were determined by measuring monocyte chemotactic activity after adding rabbit lipoproteins to human endothelial cells. HDL-inflammatory index (HII) and LDL-inflammatory index (LII), respectively, were 1.39 +/- 0.24; 1.35 +/- 0.29 (vehicle), 0.67 +/- 0.26; 0.63 +/- 0.38 (D-4F) (P < 0.001 vs. vehicle), and 0.67 +/- 0.2; 0.68 +/- 0.32 (L-4F) (P < 0.01 vs. vehicle). Serum amyloid A (SAA) levels were 95 +/- 39, 8 +/- 22, and 7 +/- 19 mug/ml, respectively, for vehicle, D-4F, and L-4F (P < 0.001 vs. vehicle). There was no correlation between lesion area and total plasma or HDL-cholesterol levels. In contrast, there was a positive correlation with HII, LII, and SAA (P = 0.002, P = 0.0026, P = 0.0079, respectively). HII correlated closely with SAA levels (r = 0.6616; r(2) = 0.4377, P < 0.0001). Thus, HII, LII, and SAA are better predictors of lesion area than are total plasma or HDL-cholesterol levels in cholesterol-fed rabbits.
Assuntos
Colesterol na Dieta/farmacologia , Doença da Artéria Coronariana/patologia , Inflamação/induzido quimicamente , Proteína Amiloide A Sérica/metabolismo , Animais , Aorta/patologia , Apolipoproteína A-I/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dieta Aterogênica , Feminino , Mimetismo Molecular , Peptídeos/farmacologia , Coelhos , Triglicerídeos/sangueRESUMO
Over the past decade evidence has accumulated that suggests that the anti-inflammatory properties of HDL may be at least as important as the levels of HDL-cholesterol. The recent failure of the torcetrapib clinical trails has highlighted the potential differences between HDL-cholesterol levels and HDL function. Agents to improve HDL function including HDL anti-inflammatory properties provide a new therapeutic strategy for ameliorating atherosclerosis and other chronic inflammatory conditions related to dyslipidemia. Seeking guidance from the structure of the apolipoproteins of the plasma lipoproteins has allowed the creation of a series of polypeptides that have interesting functionality with therapeutic implications. In animal models of atherosclerosis, peptide mimetics of apolipoproteins have been shown to improve the anti-inflammatory properties of HDL, significantly reduce lesions and improve vascular inflammation and function without necessarily altering HDL-cholesterol levels. Some of these are now entering the clinical arena as interventions in pharmacologic and pharmacodynamic studies.
RESUMO
PURPOSE OF REVIEW: To determine the potential clinical utility of high-density lipoprotein-mimetic peptides. RECENT FINDINGS: Oral administration of D-4F together with pravastatin caused lesion regression in old apoE null mice. Administration of D-4F to low-density lipoprotein receptor null mice fed a Western diet reduced the association of myeloperoxidase with apoA-I and reduced the 3-nitrotyrosine content of apoA-I. Oral D-4F improved arterial vasoreactivity independent of apoA-I. Mice genetically lacking apoA-I showed significant improvement in vasoreactivity but, in contrast to mice with apoA-I, did not demonstrate reduced arterial wall thickness after D-4F treatment. In a rat model of diabetes, D-4F administration induced heme oxygenase-1 and extracellular superoxide dismutase, prevented endothelial sloughing, and dramatically improved arterial vasoreactivity. A peptide with 10 D-amino acid residues taken from the sequence of apoJ rendered high-density lipoprotein anti-inflammatory in mice and monkeys, and dramatically reduced atherosclerosis in apoE null mice. Oral administration of tetrapeptides synthesized from either L-amino acids or D-amino acids rendered high-density lipoprotein anti-inflammatory in mice and monkeys, and reduced atherosclerosis in apoE null mice. SUMMARY: Peptides that sequester lipoprotein lipid hydroperoxides release a series of high-density lipoprotein-associated antioxidant enzymes such as paraoxonase from inhibition and protect apoA-I from oxidative damage that would impair cholesterol efflux.
Assuntos
Anti-Inflamatórios/farmacologia , Aterosclerose/tratamento farmacológico , Materiais Biomiméticos/farmacologia , Lipoproteínas HDL/química , Peptídeos/farmacologia , Animais , Anti-Inflamatórios/química , Apolipoproteínas/genética , Materiais Biomiméticos/química , Lipoproteínas HDL/genética , Peptídeos/química , Peptídeos/genéticaRESUMO
OBJECTIVE: To determine the properties of a peptide synthesized from D-amino acids corresponding to residues 113 to 122 in apolipoprotein (apo) J. METHODS AND RESULTS: In contrast to D-4F, D- [113-122]apoJ showed minimal self-association and helicity in the absence of lipids. D-4F increased the concentration of apoA-I with pre-beta mobility in apoE-null mice whereas D- [113-122]apoJ did not. After an oral dose D- [113-122]apoJ more slowly associated with lipoproteins and was cleared from plasma much more slowly than D-4F. D- [113-122]apoJ significantly improved the ability of plasma to promote cholesterol efflux and improved high-density lipoprotein (HDL) inflammatory properties for up to 48 hours after a single oral dose in apoE-null mice, whereas scrambled D- [113-122]apoJ did not. Oral administration of 125 microg/mouse/d of D- [113-122]apoJ reduced atherosclerosis in apoE-null mice (70.2% reduction in aortic root sinus lesion area, P=4.3 x 10(-13); 70.5% reduction by en face analysis, P=1.5 x 10(-6)). In monkeys, oral D- [113-122]apoJ rapidly reduced lipoprotein lipid hydroperoxides (LOOH) and improved HDL inflammatory properties. Adding 250 ng/mL of D-[113-122]apoJ (but not scrambled D- [113-122]apoJ) to plasma in vitro reduced LOOH and increased paraoxonase activity. CONCLUSIONS: Oral D- [113-122]apoJ significantly improves HDL inflammatory properties in mice and monkeys and inhibits lesion formation in apoE-null mice.
Assuntos
Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Clusterina/farmacologia , Lipoproteínas HDL/imunologia , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Apolipoproteína A-I/farmacologia , Artérias/citologia , Arildialquilfosfatase/metabolismo , Aterosclerose/genética , Proteínas Sanguíneas/farmacologia , Células Cultivadas , Clusterina/síntese química , Feminino , Humanos , Técnicas In Vitro , Peroxidação de Lipídeos/efeitos dos fármacos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/farmacologiaRESUMO
PURPOSE OF REVIEW: Recent publications related to the potential use of apolipoprotein (apo)A-I and apoA-I mimetic peptides in the treatment of atherosclerosis are reviewed. RECENT FINDINGS: A preliminary report indicating that infusion of apoA-IMilano into humans once weekly for 5 weeks caused a significant decrease in coronary artery atheroma volume has sparked great interest in the potential therapeutic use of apoA-I. Recent studies have revealed that HDL quality (e.g. HDL apolipoprotein and lipid content, including oxidized lipids, particle size and electrophoretic mobility, associated enzymatic activities, inflammatory/anti-inflammatory properties, and ability to promote cholesterol efflux) may be more important than HDL-cholesterol levels. Therefore, when developing new strategies to raise HDL-cholesterol concentrations by interfering with HDL metabolism, one must consider the quality of the resulting HDL. In animal models, raising HDL-cholesterol levels by administering oral phospholipids improved both the quantity and quality of HDL and was associated with lesion regression. An apoA-I mimetic peptide, namely 4F synthesized from D-amino acids (D-4F), administered orally to mice did not raise HDL-cholesterol concentrations but promoted the formation of pre-beta HDL containing increased paraoxonase activity, resulting in significant improvements in HDL's anti-inflammatory properties and ability to promote cholesterol efflux from macrophages in vitro. Oral D-4F also promoted reverse cholesterol efflux from macrophages in vivo. SUMMARY: The quality of HDL may be more important than HDL-cholesterol levels. ApoA-I and apoA-I mimetic peptides appear to have significant therapeutic potential in atherosclerosis.
Assuntos
Apolipoproteína A-I/uso terapêutico , Arteriosclerose/tratamento farmacológico , Peptídeos/uso terapêutico , Animais , Apolipoproteína A-I/administração & dosagem , Apolipoproteína A-I/química , HDL-Colesterol/química , HDL-Colesterol/fisiologia , Humanos , Camundongos , Mimetismo Molecular , Peptídeos/química , Peptídeos/farmacologiaRESUMO
BACKGROUND: Evidence suggests that apolipoprotein A-I (apoA-I) and HDL play important roles in modulating inflammation. We previously reported that an apoA-I mimetic peptide, D-4F, reduced inflammatory responses to influenza virus in mice. To further define the antiinflammatory activity of D-4F, a human alveolar type II cell line, A549, was used. METHODS AND RESULTS: Cells were either uninfected or infected with influenza A in the presence or absence of D-4F. Cells treated with D-4F were more viable, and virus-induced cytokine production was suppressed by D-4F. Caspases associated with cytokine production were activated after infection but suppressed by D-4F treatment. Infected A549 cells showed dramatic increases in cellular phospholipid secretion into the media. When infected cells were incubated with D-4F, secretion of parent nonoxidized, noninflammatory phospholipids was unaltered, but production of proinflammatory oxidized phospholipids was inhibited. CONCLUSIONS: Type II pneumocytes respond to influenza A infection by activating caspases and secreting cytokines and cellular phospholipids into the extracellular environment, including oxidized phospholipids that evoke inflammatory responses. D-4F treatment inhibited these events. Our results suggest that apoA-I and apoA-I mimetic peptides such as D-4F are antiinflammatory agents that may have therapeutic potential.
Assuntos
Inflamação/prevenção & controle , Vírus da Influenza A/fisiologia , Peptídeos/farmacologia , Alvéolos Pulmonares/citologia , Adenocarcinoma/patologia , Apolipoproteína A-I , Linhagem Celular Tumoral/metabolismo , Linhagem Celular Tumoral/patologia , Linhagem Celular Tumoral/virologia , Cisteína Endopeptidases/análise , Citocinas/análise , Depressão Química , Ativação Enzimática/efeitos dos fármacos , Humanos , Inflamação/virologia , Interferon-alfa/biossíntese , Interferon beta/biossíntese , Interleucina-6/biossíntese , Lipoproteínas LDL/química , Neoplasias Pulmonares/patologia , Oxirredução , Fosfolipídeos/análise , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: We reported that HDL loses its antiinflammatory properties during acute influenza A infection in mice, and we hypothesized that these changes might be associated with increased trafficking of macrophages into the artery wall. The present study tested this hypothesis. METHODS AND RESULTS: D-4F, an apolipoprotein A-I mimetic peptide, or vehicle in which it was dissolved (PBS) was administered daily to LDL receptor-null mice after a Western diet and after influenza infection. D-4F treatment increased plasma HDL cholesterol and paraoxonase activity compared with PBS and inhibited increases in LDL cholesterol and peak levels of interleukin-6 after infection. Lung viral titers were reduced by 50% in mice receiving D-4F. Injection of female mice with male macrophages, which were detected with real-time polymerase chain reaction to measure the male Sry gene, revealed a marked increase in macrophage traffic into the aortic arch and innominate arteries after infection that was prevented by administration of D-4F. CONCLUSIONS: We conclude that loss of antiinflammatory properties of HDL after influenza infection in mice is associated with increased arterial macrophage traffic that can be prevented by administration of D-4F.
Assuntos
Apolipoproteína A-I/análogos & derivados , Apolipoproteína A-I/farmacologia , Movimento Celular/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Peptídeos/farmacologia , Animais , Aorta Torácica/patologia , Arildialquilfosfatase , Comportamento Animal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Tronco Braquiocefálico/patologia , Movimento Celular/imunologia , Células Cultivadas , Dieta Aterogênica , Esterases/metabolismo , Feminino , Genes sry/genética , Técnicas In Vitro , Interleucina-6/sangue , Interleucina-6/metabolismo , Lipoproteínas HDL/sangue , Lipoproteínas HDL/fisiologia , Lipoproteínas LDL/sangue , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/transplante , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/fisiopatologia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/patologia , Receptores de LDL/deficiência , Receptores de LDL/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Replicação Viral/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: To summarize the recent evidence on the physiological relevance of the view that LDL lipid oxidation may play a major role in the inflammatory reaction that leads to or amplifies atherogenesis. Oxidation of LDL phospholipids containing arachidonic acid at the sn-2 position occurs when a critical concentration of 'seeding molecules' derived from the lipoxygenase pathway is reached in LDL. This generates a series of biologically active, oxidized phospholipids that mediate the cellular events seen in the developing fatty streak. RECENT FINDINGS: We have observed that LDL from mice that are genetically predisposed to diet-induced atherosclerosis is highly proinflammatory when the mice are maintained on an atherogenic diet, when they are injected with LDL-derived oxidized phospholipids, or once they are infected with influenza A virus. Patients with coronary atherosclerosis also had highly proinflammatory LDL, despite having normal blood lipid levels or normal plasma HDL levels. SUMMARY: We and others have hypothesized that HDL and LDL-derived oxidized phospholipids may be part of a system of nonspecific innate immunity. We therefore propose that determination of HDL capacity against LDL oxidation and the detection of proinflammatory HDL may be a useful marker of susceptibility to atherosclerosis.