RESUMO
CD36 is recognized as a lipid and fatty acid receptor and plays an important role in the metabolic syndrome and associated cardiac events. The pleiotropic activity and the multiple molecular associations of this scavenger receptor with membrane associated molecules in different cells and tissues have however questioned its potential as a therapeutic target. The present study shows that it is possible to identify low molecular weight chemicals that can block the CD36 binding and uptake functions. These inhibitors were able to reduce arterial lipid deposition, fatty acid intestinal transit, plasma concentration of triglycerides and glucose, to improve insulin sensitivity, glucose tolerance and to reduce the plasma concentration of HbAc1 in different and independent rodent models. Correlation between the anti-CD36 activity of these inhibitors and the known pathophysiological activity of this scavenger receptor in the development of atherosclerosis and diabetes were observed at pharmacological doses. Thus, CD36 might represent an attractive therapeutic target.
Assuntos
Aterosclerose/prevenção & controle , Antígenos CD36/metabolismo , Complicações do Diabetes/prevenção & controle , Dislipidemias/prevenção & controle , Hipertrigliceridemia/metabolismo , Tiofenos/farmacologia , Animais , Aterosclerose/etiologia , Benzimidazóis , Antígenos CD36/genética , Linhagem Celular , Modelos Animais de Doenças , Dislipidemias/etiologia , Humanos , Hipertrigliceridemia/tratamento farmacológico , Resistência à Insulina , Masculino , Camundongos , Período Pós-Prandial , Ratos , Ratos Wistar , Tiofenos/administração & dosagemRESUMO
BACKGROUND: Oxidized low-density lipoprotein (LDL) is associated with cardiovascular disease. Macrophages contribute to LDL oxidation, and oxidized LDL (oxLDL) affects macrophage function. We searched for the strongest gene correlates of oxLDL in macrophages in coronary plaques and studied the effect of oxLDL on their expression in THP-1 cells. METHODS AND RESULTS: Gene expression in macrophages isolated from coronary plaque macrophages from hypercholesterolemic swine was measured on Agilent Human cDNA microarrays. Compared with a universal reference, 1653 transcripts were deregulated. The expression of 11 genes correlated positively and the expression of 5 genes correlated negatively with plaque oxLDL. Interferon regulatory factor-1 (IRF1; R2 = 0.69) and toll-like receptor 2 (TLR2; R2 = 0.18) were the strongest positive correlates of oxLDL. Superoxide dismutase 1 (SOD1) was the strongest inverse correlate of oxLDL (R2 = 0.57). Immunohistochemical analysis showed colocalization of IRF1, TLR2, and SOD1 protein in macrophages and confirmed the RNA expression data. OxLDL-induced foam cell formation in THP-1 macrophages was associated with increased expression of IRF1 and TLR2 and decreased expression of SOD1. CONCLUSIONS: Our data support the hypothesis that oxLDL is a proinflammatory stimulus that induces the expression of TLR2 and IRF1, 2 important gene regulators of innate immune response, and inhibits the expression of the antioxidant SOD1.
Assuntos
Doença da Artéria Coronariana/metabolismo , Hipercolesterolemia/metabolismo , Fator Regulador 1 de Interferon/metabolismo , Lipoproteínas LDL/metabolismo , Superóxido Dismutase/metabolismo , Receptor 2 Toll-Like/metabolismo , Idoso , Animais , Linhagem Celular , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Expressão Gênica , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase-1 , Suínos , Porco MiniaturaRESUMO
BACKGROUND: Weight loss in obese insulin-resistant but not in insulin-sensitive persons reduces coronary heart disease risk. To what extent changes in gene expression are related to atherosclerosis and cardiovascular function is unknown. METHODS AND RESULTS: We studied the effect of diet restriction-induced weight loss on gene expression in the adipose tissue, the heart, and the aortic arch and on atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia, and insulin resistance are associated with hypertension, impaired left ventricular function, and accelerated atherosclerosis in those mice. Compared with lean mice, peroxisome proliferator-activated receptors (PPAR)-alpha and PPAR-gamma expression was downregulated in obese double-knockout mice. Diet restriction caused a 45% weight loss, an upregulation of PPAR-alpha and PPAR-gamma, and a change in the expression of genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress, and inflammation, most of which are under the transcriptional control of these PPARs. Changes in gene expression were associated with increased insulin sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. PPAR-alpha and PPAR-gamma expression was inversely related to plaque volume and to oxidized LDL content in the plaques. CONCLUSIONS: Induction of PPAR-alpha and PPAR-gamma in adipose tissue, heart, and aortic arch is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight loss. Improved lipid metabolism and insulin signaling is associated with decreased tissue deposition of oxidized LDL that increases cardiovascular risk in persons with the metabolic syndrome.
Assuntos
Arteriosclerose/prevenção & controle , Regulação da Expressão Gênica/fisiologia , Resistência à Insulina , Obesidade/dietoterapia , PPAR alfa/biossíntese , PPAR gama/biossíntese , Regulação para Cima , Redução de Peso , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Aorta Torácica/metabolismo , Arteriosclerose/etiologia , Arteriosclerose/genética , Arteriosclerose/metabolismo , Autoanticorpos/análise , Ritmo Circadiano , Ecocardiografia , Genótipo , Glucose/metabolismo , Testes de Função Cardíaca , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/prevenção & controle , Inflamação , Leptina/deficiência , Leptina/genética , Lipoproteínas LDL/análise , Lipoproteínas LDL/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Miocárdio/metabolismo , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , Estresse Oxidativo , PPAR alfa/genética , PPAR gama/genética , Receptores de LDL/deficiência , Receptores de LDL/genética , Transcrição GênicaRESUMO
Genome-wide studies have recently revealed the unexpected complexity of the genetic response to apparently simple physiological changes. Here, we show that when yeast cells are exposed to Cd(2+), most of the sulfur assimilated by the cells is converted into glutathione, a thiol-metabolite essential for detoxification. Cells adapt to this vital metabolite requirement by modifying globally their proteome to reduce the production of abundant sulfur-rich proteins. In particular, some abundant glycolytic enzymes are replaced by sulfur-depleted isozymes. This global change in protein expression allows an overall sulfur amino acid saving of 30%. This proteomic adaptation is essentially regulated at the mRNA level. The main transcriptional activator of the sulfate assimilation pathway, Met4p, plays an essential role in this sulfur-sparing response.