| Autor: |
Huisamen, B, Strijdom, H, Collop, N, Espach, Y |
| Předmět: |
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| Zdroj: |
Cardiovascular Research; Jul2014, Vol. 103 Issue suppl_1, pS118-S118, 1p |
| Abstrakt: |
Ataxia-telangiectasie (A-T) is an autosomal recessive disorder that is caused by mutations in the ATM (ataxia-telengtiectasie mutated) gene. The gene product, ATM, is a 350kDa serine/threonine protein kinase belonging to the family of phosphatidylinositol-3 kinase like kinases (PIKK) and has a large number of substrates in various signalling pathways. ATM can be localized to the nuclear, cytosolic or mitochondrial compartments of a cell. Patients suffering from A-T have either no or very low expression of ATM and display a very high incidence of insulin resistance or type 2 diabetes mellitus and are more susceptible to ischaemic heart disease. ATM is activated by insulin, hypoxia, DNA-strand breaks or oxidative stress and has been implicated in the development of cancer, metabolic disorders, low anti-oxidant defence and atherosclerosis. Because of scant information on (i) the role of ATM in signalling cascades especially in the heart, (ii) the possible cardiovascular effects of ATM and (iii) evidence that obesity may alter the expression of ATM, we aimed to investigate the expression and impact of ATM in the heart in the context of obesity-induced insulin resistance.Methods: Wistar rats were rendered obese and insulin resistant (DIO) by feeding a diet supplemented with sugar and fat for a period of 16 weeks. Glucose tolerance, fasting insulin and glucose levels were determined and, after sacrifice, body weight and intra-peritoneal fat weight of the animals. Ventricular cardiomyocytes were prepared by perfusion-digestion and insulin responses measured using accumulation of [3H]2-deoxyglucose. The specific ATM inhibitor KU60019 was used to manipulate activity of the protein. Expression of ATM was determined by Western blotting and specific, commercially available antibodies. Cardiac mitochondria were prepared by differential centrifugation and their oxidative capacity determined using a Clark-type electrode. Cardiac micro-vascular endothelial cells were purchased commercially.Results: We have demonstrated for the first time that: (i) the expression of ATM is downregulated in the heart in obesity/insulin resistance; (ii) Inhibition of ATM in cardiomyocytes attenuates insulin-stimulated glucose uptake; (iii) ATM is expressed in cardiac microvascular endothelial cells; (iv) ATM is also localized to myocardial mitochondria and (v) its expression is downregulated in mitochondria from hearts of obese animals that also display mitochondrial dysfunction.We conclude that ATM is a potential roleplayer in the development of a diabetic cardiomyopathy [ABSTRACT FROM PUBLISHER] |
| Databáze: |
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