RESUMEN
OBJECTIVE: Inflammatory processes play an important role in atherosclerosis, and increasing evidence implies that microbial pathogens and proinflammatory cytokines are involved in the development and activation of atherosclerotic lesions. To find new inflammatory genes, we explored the vascular transcriptional response to an activator of innate immunity bacterial lipopolysaccharides (LPSs). METHODS AND RESULTS: Gene arrays identified the cytomegalovirus-inducible gene 5 (cig5)/viperin among the genes most potently induced by LPS in human vascular biopsies. Viperin was expressed by endothelial cells in atherosclerotic arteries and significantly elevated in atherosclerotic compared with normal arteries. In culture, cytomegalovirus infection, interferon-gamma, and LPS induced viperin expression. CONCLUSIONS: Viperin is expressed in atherosclerosis and induced in vascular cells by inflammatory stimuli and cytomegalovirus infection. The putative functions of viperin in atherosclerosis may relate to disease-associated microbes.
Asunto(s)
Enfermedades de las Arterias Carótidas/fisiopatología , Infecciones por Citomegalovirus/fisiopatología , Citomegalovirus/genética , Proteínas/genética , Vasculitis/fisiopatología , Animales , Apolipoproteínas E/genética , Biopsia , Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/inmunología , Enfermedades de las Arterias Carótidas/patología , Células Cultivadas , Vasos Coronarios/citología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/patología , Endotelio Vascular/citología , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Humanos , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Músculo Liso Vascular/citología , Análisis de Secuencia por Matrices de Oligonucleótidos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Arteria Renal/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Venas Umbilicales/citología , Vasculitis/inmunología , Vasculitis/patologíaRESUMEN
BACKGROUND: A significant number of patients with chronic obstructive pulmonary disease (COPD) exhibit skeletal muscle wasting and decreased capillary area formation, which correlate with increased mortality. AIM: To determine the molecular mechanisms mediating decreased capillary formation in COPD. METHODS: 24 patients with COPD and 12 matching controls were recruited. Patients with COPD were classified into mild, moderate and severe groups according to GOLD (global initiative for chronic obstructive lung disease) criteria. Biopsy specimens were obtained from the tibialis anterior muscle. Fibre typing and capillary formation, together with messenger RNA (mRNA) expression of hypoxia-inducible factors (HIF1alpha and HIF3alpha), vascular endothelial growth factors (VEGF-A, VEGF-B and VEGF-C isoforms) and von Hippel-Lindau (VHL) protein, were determined. VHL expression and localisation were further studied by immunohistochemistry. RESULTS: Skeletal muscle capillary formation decreased significantly with increasing disease severity. Compared with controls, a tendency to mRNA overexpression of HIF1alpha, HIF3alpha and VEGF isoforms was observed in mild and moderate COPD, which decreased at the severe stage. In contrast, skeletal muscle biopsy samples from patients with COPD exhibited significant overexpression of VHL at both the mRNA and protein level by immunohistochemistry. VHL protein was further determined to be localised to satellite cells. CONCLUSIONS: Overexpression of VHL was identified in the skeletal muscle of patients with COPD. Increased VHL activity may have a negative effect on transduction of the hypoxic signal and may contribute to decreased capillarisation in skeletal muscles of patients with COPD.