RESUMEN
Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role.
Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Regulación de la Expresión Génica , Variación Genética , Proteínas Desacopladoras Mitocondriales/genética , Peptidil-Dipeptidasa A/genética , Transducción de Señal , Adolescente , Adulto , Alelos , Diabetes Mellitus Tipo 1/genética , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role.
RESUMEN
BACKGROUND: A substantial proportion of patients suffer prolonged length of intensive care unit stay (PLOS) or prolonged mechanical ventilation (PMV) following coronary artery bypass grafting (CABG). Identifying factors associated with PLOS and PMV would aid in patient risk stratification. We sought to identify the factors associated with PLOS and PMV following CABG. METHODS: Participants were patients undergoing first-time elective CABG. All were observed until discharge and clinical data were collected on a standardized proforma. PLOS and PMV were defined a priori as >2 days and >12 h respectively, based on centre norms. RESULTS: Of the 439 patients in the study, 105 (23.9%) had PLOS and 111 (25.2%) had PMV. Independent predictors of PMV were age, diabetes, previous myocardial infarction (MI), New York Heart Association (NYHA) class and statin use. The only independent predictor of PLOS was the duration of preceding hypertension. CONCLUSION: The factors associated with PMV and PLOS in our study are easily attainable, routine clinical details and may be built into bed management algorithms. Confirmation of the association of preceding hypertension and subsequent investigation of the possible mechanism mediating this association, is suggested.
Asunto(s)
Hipertensión/epidemiología , Hipertensión/terapia , Unidades de Cuidados Intensivos/tendencias , Tiempo de Internación/tendencias , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Respiración Artificial/efectos adversos , Respiración Artificial/tendencias , Factores de Riesgo , Factores de TiempoRESUMEN
Large increases in inflammatory markers, particularly IL-6, occur after cardiac surgery. However, despite interventions to reduce the inflammatory response, great variability still remains which could in part be attributable to genetic predisposition. Since increased IL-6 levels following surgery are also associated with poorer outcome we sought to determine whether baseline and post-operative levels of Interleukin-6 (IL-6) and functional common variants of the Interleukin-6 (IL6) gene are associated with post-operative outcome following coronary artery bypass grafting (CABG). Caucasian patients undergoing first-time elective CABG were studied. IL-6 levels were measured pre-, 6h and 24h following surgery and genotypes for IL6 gene variants -174G>C and -572G>C were obtained. Clinical data was collected daily until patient discharge. Patient outcome was categorised as with (ICUC, n=177) and without (NICUC, n=189) a post-operative complication during the ICU period and with (POC, n=215) and without (NC, n=151) a post-operative complication during hospitalisation. IL-6 levels pre- and at 24h were greater in POC and ICUC than NC and NICUC, respectively. Pre- IL-6 levels independently predicted (for 1 standard deviation increase in log IL-6) POC (OR 1.4, 95% CI 1.1-1.7, p=0.008) and ICUC (OR 1.3, 95% CI 1.0-1.6, p=0.02) outcomes. Overall, the IL6-572G>C had an effect over time on IL-6 levels (p=0.04) and on IL-6 levels in NC (P=0.008) and NICUC (p=0.006). However, no associations were found with the IL6 -572G>C or -174G>C variants on IL-6 levels at individual time-points or by outcome group. Thus, in conclusion, elevated pre-operative IL-6 levels, but not IL6 gene variants predict poor patient outcome following CABG.
Asunto(s)
Puente de Arteria Coronaria/efectos adversos , Inflamación/inmunología , Interleucina-6/sangre , Anciano , Biomarcadores/sangre , Procedimientos Quirúrgicos Electivos , Femenino , Predisposición Genética a la Enfermedad , Humanos , Inflamación/genética , Interleucina-6/genética , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba , Población Blanca/genéticaRESUMEN
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may have anti-inflammatory actions, an effect that could explain some of their beneficial effects on cardiovascular events in clinical trials. Coronary artery bypass grafting (CABG) is associated with a systemic inflammatory response and provides a convenient model to examine the effects of such agents. Genetic polymorphisms may be important in influencing the expression of cytokines, such as interleukin-6 (IL-6). We randomized men awaiting CABG to treatment with enalapril, losartan, or control for 2 months before surgery. Systemic IL-6, IL-8, IL-10, and IL-1 receptor agonists were measured before and after surgery, and genotypes for the -174 G/C and -572 G/C IL-6 gene polymorphisms were determined. Total release of the IL-1 receptor agonist was decreased 29% by enalapril and 31% by losartan (adjusted p = 0.041). IL-6 was decreased 17% by enalapril and 20% by losartan. Subjects possessing the -174 GG genotype produced 20% more IL-6 (adjusted p = 0.029). In these high producers of IL-6, release of IL-6 was decreased 51% by enalapril (adjusted p = 0.001) and 32% by losartan (adjusted p = 0.068). Release of IL-10 was nonsignificantly decreased 26% by enalapril and 21% by losartan, whereas IL-8 was not detected. In conclusion, enalapril and losartan significantly decreased release of the IL-1 receptor agonist after CABG. Enalapril produced a highly significant decrease of 51% in the release of IL-6 in patients identified as high producers of IL-6 by the -174 G/C polymorphism, whereas losartan has a similar but less marked effect. The production of IL-6 in this setting is influenced by the -174 G/C polymorphism.
Asunto(s)
Angina de Pecho/inmunología , Antihipertensivos/farmacología , Citocinas/efectos de los fármacos , Enalapril/farmacología , Interleucina-6/genética , Losartán/farmacología , Anciano , Angina de Pecho/tratamiento farmacológico , Angina de Pecho/genética , Angina de Pecho/cirugía , Puente de Arteria Coronaria , Citocinas/sangre , Citocinas/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
Interleukin-6 (IL-6) is a pro-inflammatory cytokine and major mediator of the acute phase response. Single nucleotide polymorphisms within the 5' flanking region (-597G>A, -572G>C and -174G>C) have previously been associated with increased risk of coronary heart disease and influencing transcription of IL-6 both in vitro and in vivo. In addition to these, a polymorphic AnTn tract is also present in the promoter of IL-6. Analysis in five different primate species demonstrated a G allele at -597, -572 and -174 in all species. By contrast, the AnTn tract was polymorphic in at least three species, and was roughly conserved in overall length despite an increase in the relative proportion of A versus T in the evolution of the human sequence from that in the ancestor of the great apes. The effect of the AnTn polymorphism on IL-6 levels was examined following coronary artery bypass graft surgery (CABG), a known inflammatory stimulus for IL-6 production. One hundred and thirty-two patients undergoing CABG were genotyped for the AnTn tract by automated sequencing. Four alleles were identified: A8T12 (allele frequency 0.35, 95% CI 0.29-0.40); A9T11 (0.26, 0.21-0.31); A10T11 (0.21, 0.16-0.26); and A10T10 (0.18, 0.14-0.23). Isolation of the effect of different alleles of the AnTn tract on an identical haplotypic background for the other polymorphisms in the promoter showed that individuals homozygous for A9T11 had significantly higher post-operative IL-6 levels than A10T11 homozygotes (275 +/- 46 pg/ml versus 152 +/- 29; P=0.04). The effect of the A8T12 allele could not be determined separately due to strong allelic association with -174C. The conserved length of the AnTn tract and the association in vivo with IL-6 levels strongly suggest the functionality of the tract on IL-6 expression, independent of contributions from other polymorphic sites within the promoter.
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Puente de Arteria Coronaria , Interleucina-6/genética , Polimorfismo de Nucleótido Simple/genética , Animales , Secuencia de Bases , Regulación de la Expresión Génica , Genotipo , Gorilla gorilla , Haplotipos , Humanos , Interleucina-6/sangre , Datos de Secuencia Molecular , Pan paniscus , Pan troglodytes , Papio , Filogenia , Pongo pygmaeus , Primates/genética , Regiones Promotoras GenéticasRESUMEN
The objective of this study was to examine the relationship between the interleukin-6 (IL-6) -174 G>C promoter polymorphism and exercise-induced femoral cortical bone resorption. Skeletal response to exercise was assessed in 130 male Caucasian army recruits. Five cross-sectional magnetic resonance images of the right femur were obtained before and after a 10-week period of basic physical training, and changes in cross-sectional cortical area were calculated. Recruits were genotyped for the -174 G>C IL-6 promoter polymorphism. Genotype frequencies (GG 36%, GC 47%, CC 22.17%) were in Hardy-Weinberg equilibrium. The mean percentage change in proximal femoral cross-sectional cortical area was strongly IL-6 genotype-dependent, with GG homozygotes losing 6.8 (3.82)% in cortical area, GC gaining+5.5 (4.88)% and CC gaining+17.3 (9.46)% (P=0.007 for linear trend). These changes persisted throughout the right femur and were significant in the femur as a whole (P=0.03). This study demonstrates an association between a functional polymorphism in the IL-6 gene and femoral cortical remodelling during strenuous physical exercise. Previous studies have suggested an important role for IL-6 in the regulation of bone mass in postmenopausal women, and in the invasion of bone by metastatic tumour deposits. These data extend these observations to the regulation of bone mass in healthy males, supporting a fundamental role for IL-6 in the regulation of bone mass and bone remodelling in humans.
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Densidad Ósea/genética , Resorción Ósea/genética , Ejercicio Físico , Fémur/fisiopatología , Predisposición Genética a la Enfermedad/genética , Interleucina-6/genética , Polimorfismo Genético , Adulto , Resorción Ósea/metabolismo , Fémur/metabolismo , Genotipo , Humanos , Interleucina-6/metabolismo , Masculino , Personal Militar , Reino UnidoRESUMEN
OBJECTIVE: Cyclooxygenase (COX)-2 is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. We investigated the COX-2 gene for functional variants that may influence susceptibility to disease. METHODS AND RESULTS: The promoter of COX-2 was screened for variants in healthy subjects by use of polymerase chain reaction-based methods. Promoter activity was investigated by using reporter expression experiments in human lung fibroblasts. Patients undergoing coronary artery bypass graft surgery, with measurements of plasma markers linked to COX-2 activity, were genotyped for association studies. A common COX-2 promoter variant, -765G>C, was found and shown to be carried by >25% of a group of healthy UK subjects. The -765C allele had significantly lower promoter activity compared with -765G, basally (28+/-3% lower, P<0.005) and in serum-stimulated cells (31+/-2% lower, P<0.005). In patients subjected to coronary artery bypass graft surgery, the magnitude of rise in levels of C-reactive protein (CRP) was strongly genotype dependent. Compared with -765G homozygotes, patients carrying the -765C allele had significantly lower plasma CRP levels at 1 to 4 days after surgery (14% lower at the peak of CRP levels on day 3, P<0.05 for all time points). CONCLUSIONS: For several acute and chronic inflammatory diseases, -765G>C may influence the variability of response observed.