Publications (215) View all
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Article: Nox1 Plays a Key Role in Diabetes Accelerated Atherosclerosis.
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ABSTRACT: BACKGROUND: In diabetes mellitus, vascular complications such as atherosclerosis are a major cause of death. The key underlying pathomechanisms are unclear. However, hyperglycemic oxidative stress appears to play a role with NADPH oxidase (Nox), the only known dedicated enzyme to generate ROS. Here we identify the Nox1 isoform as playing a key and pharmacologically targetable role in the accelerated development of diabetic atherosclerosis. METHODS AND RESULTS: Human aortic endothelial cells exposed to hyperglycemic conditions showed increased expression of Nox1, oxidative stress and proinflammatory markers in a Nox1-siRNA reversible manner. Similarly, the specific Nox inhibitor, GKT137831, prevented oxidative stress in response to hyperglycaemia in human aortic endothelial cells. To examine these observations in vivo, we investigated the role of Nox1 on plaque development in ApoE(-/-) mice 10 weeks after induction of diabetes. Deletion of Nox1, but not Nox4, had a profound anti-atherosclerotic effect correlating with reduced ROS formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration and reduced expression of pro-inflammatory and pro-fibrotic markers. Similarly, treatment of diabetic ApoE(-/-) mice with GKT137831 attenuated atherosclerosis development. CONCLUSIONS: These studies identify a major pathological role for Nox1 and suggest that Nox1-dependent oxidative stress is a promising target for diabetic vasculopathies including atherosclerosis.Circulation 04/2013; · 14.74 Impact Factor -
Article: Tandem Inhibition of PKC in Diαβetic Nephropathy: It Takes Two to Tango?
Diabetes 04/2013; 62(4):1010-1. · 8.29 Impact Factor -
Article: Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure.
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ABSTRACT: Abstract Background: High levels of circulating advanced glycation end products (AGEs) can initiate chronic low-grade activation of the immune system (CLAIS) with each of these factors independently associated with cardiovascular (CV) morbidity and mortality. Therefore, our objective was to characterize the relationship between serum AGEs, CLAIS and other risk factors for CV disease in normotensive non-diabetic individuals. Methods: We measured body mass index (BMI), waist-to-hip ratio (WHR), blood pressure, lipid and glucose profile in 44 non-diabetic volunteers (17 female, 27 males). Carboxymethyl-lysine (CML) was measured by ELISA as a marker for circulating AGEs and NF-κB p65 activity as an inflammatory marker by DNA-binding in peripheral blood mononuclear cells lysates (PBMC). Results: Plasma CML concentrations were related to diastolic blood pressure (r=-0.51, p<0.01) independently of age, sex, BMI and WHR (p<0.05). Diastolic blood pressure was also related to NF-κB activity in PBMC (r=0.47, p<0.01) before and after adjustment for age, sex, BMI and WHR (p<0.05). Plasma CML concentrations were related to the pulse pressure before (r=0.42; p<0.05) and after adjustment for age, sex, BMI and waist (p<0.05). Neither CML nor NF-κB activity were related to systolic blood pressure (both p=ns). Plasma CML concentrations were not associated with plasma lipid or glucose concentrations (all p=ns). Conclusions: Plasma AGE levels and NF-κB activity in PBMC were independent determinants of diastolic and pulse pressure in healthy normotensive individuals. This association suggests a role for AGEs in the etiology of hypertension, possibly via the initiation of CLAIS and aortic stiffening.Clinical Chemistry and Laboratory Medicine 03/2013; · 2.15 Impact Factor -
Dataset: Coughlan JASN Suppl files
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Article: Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease.
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ABSTRACT: Aims: Defects in the activity of enzyme complexes of the mitochondrial respiratory chain are thought to be responsible for several disorders including renal impairment. Gene mutations which result in complex I deficiency are the most common OXPHOS disorders in humans. To determine if an abnormality in mitochondrial complex I per se is associated with development of renal disease, mice with a knockdown of the complex I gene, Ndufs6 were studied. Results: Ndufs6 mice had a partial renal cortical complex I deficiency; Ndufs6gt/gt, 32% activity and Ndufs6gt/+, 83% activity compared to WT mice. Both Ndufs6gt/+ and Ndufs6gt/gt mice exhibited hallmarks of renal disease including albuminuria, urinary excretion of kidney injury molecule-1 (Kim-1), renal fibrosis and changes in glomerular volume, with decreased capacity to generate mitochondrial ATP and superoxide from substrates oxidised via complex I. However, more advanced renal defects in Ndufs6gt/gt mice were observed in the context of a disruption in the inner mitochondrial electrochemical potential, 3-nitrotyrosine-modified mitochondrial proteins, increased urinary excretion of 15-isoprostane F2t and upregulation of antioxidant defence. Juvenile Ndufs6gt/gt mice also exhibited signs of early renal impairment with increased urinary Kim-1 excretion and elevated circulating cystatin C. Innovation: We have identified renal impairment in a mouse model of partial complex I deficiency, suggesting that even modest deficits in mitochondrial respiratory chain function may act as risk factors for chronic kidney disease. Conclusion: These studies identify for the first time that complex I deficiency as the result of interruption of Ndufs6 is an independent cause of renal impairment.Antioxidants & Redox Signaling 01/2013; · 8.20 Impact Factor
