RESUMEN
Hyperglycemia is a major risk factor for endothelial dysfunction and vascular disease, and in the current study, the link to glucose-induced abnormal intracellular Ca(2+) (Ca(i)(2+)) homeostasis was explored in bovine aortic endothelial cells in high glucose (HG; 25 mmol/l) versus low glucose (LG; 5.5 mmol/l; control). Transient receptor potential 1 (TRPC1) ion channel protein, but not TRPC3, TRPC4, or TRPC6 expression, was significantly increased in HG versus LG at 72 h. HG for 4, 24, and 72 h did not change basal Ca(i)(2+) or ATP-induced Ca(i)(2+) release; however, the amplitude of sustained Ca(i)(2+) was significantly increased at 24 and 72 h and reduced by low concentration of the putative, but nonspecific, TRPC blockers, gadolinium, SKF-96365, and 2-aminoethoxydiphenyl borate. Treatment with TRPC1 antisense significantly reduced TRPC1 protein expression and ATP-induced Ca(2+) entry in bovine aortic endothelial cells. Although the link between HG-induced changes in TRPC1 expression, enhanced Ca(2+) entry, and endothelial dysfunction require further study, the current data are suggestive that targeting these pathways may reduce the impact of HG on endothelial function.
Asunto(s)
Canales de Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Calcio/metabolismo , Células Endoteliales/metabolismo , Glucosa/farmacología , Canales Catiónicos TRPC/biosíntesis , Canales Catiónicos TRPC/genética , Adenosina Trifosfato/farmacología , Animales , Elementos sin Sentido (Genética) , Ácido Araquidónico/farmacología , Western Blotting , Compuestos de Boro/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Bovinos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Gadolinio/farmacología , Glucosa/antagonistas & inhibidores , Imidazoles/farmacología , Indicadores y ReactivosRESUMEN
AIMS/HYPOTHESIS: This study aimed to identify genes that are expressed in skeletal muscle, encode proteins with functional significance in mitochondria, and are associated with type 2 diabetes. METHODS: We screened for differentially expressed genes in skeletal muscle of Psammomys obesus (Israeli sand rats), and prioritised these on the basis of genomic localisation and bioinformatics analysis for proteins with likely mitochondrial functions. RESULTS: We identified a mitochondrial intramembrane protease, known as presenilins-associated rhomboid-like protein (PSARL) that is associated with insulin resistance and type 2 diabetes. Expression of PSARL was reduced in skeletal muscle of diabetic Psammomys obesus, and restored after exercise training to successfully treat the diabetes. PSARL gene expression in human skeletal muscle was correlated with insulin sensitivity as assessed by glucose disposal during a hyperinsulinaemic-euglycaemic clamp. In 1,031 human subjects, an amino acid substitution (Leu262Val) in PSARL was associated with increased plasma insulin concentration, a key risk factor for diabetes. Furthermore, this variant interacted strongly with age to affect insulin levels, accounting for 5% of the variation in plasma insulin in elderly subjects. CONCLUSIONS/INTERPRETATION: Variation in PSARL sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Metaloproteasas/genética , Proteínas Mitocondriales/genética , Secuencia de Aminoácidos , Animales , Secuencia Conservada , Modelos Animales de Enfermedad , Familia , Femenino , Gerbillinae , Humanos , Masculino , Mitocondrias/enzimología , Datos de Secuencia Molecular , Alineación de Secuencia , Homología de Secuencia de Aminoácido , HermanosRESUMEN
Asynchronized direct-current (DC) shock was delivered inadvertently to a 67-year-old man with ventricular tachycardia. The electrical shock, which fell on the T-wave of the ECG, accelerated the tachycardia. A synchronized DC shock then converted the accelerated tachycardia to sinus rhythm. This case emphasizes the importance of synchronizing the electrical energy delivered during ventricular tachycardia.