Oxidant-NO dependent gene regulation in dogs with type I diabetes: impact on cardiac function and metabolism

Cardiovascular Diabetology

Original Investigation

Thomas H Hintze¹  Fabio A Recchia¹  Shintaro Kinugawa¹  Caroline Ojaimi¹ 

[1] Department of Physiology, New York Medical College, 10595, Valhalla, NY, USA;

关键词: Nitric Oxide;    Coronary Blood Flow;    NADPH Oxidase Subunit;    Alloxan Injection;    Phospholipid Hydroperoxide Glutathione Peroxidase;   

DOI  :  10.1186/1475-2840-9-43

 received in 2010-05-19, accepted in 2010-08-24,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundThe mechanisms responsible for the cardiovascular mortality in type I diabetes (DM) have not been defined completely. We have shown in conscious dogs with DM that: 1) baseline coronary blood flow (CBF) was significantly decreased, 2) endothelium-dependent (ACh) coronary vasodilation was impaired, and 3) reflex cholinergic NO-dependent coronary vasodilation was selectively depressed. The most likely mechanism responsible for the depressed reflex cholinergic NO-dependent coronary vasodilation was the decreased bioactivity of NO from the vascular endothelium. The goal of this study was to investigate changes in cardiac gene expression in a canine model of alloxan-induced type 1 diabetes.MethodsMongrel dogs were chronically instrumented and the dogs were divided into two groups: one normal and the other diabetic. In the diabetic group, the dogs were injected with alloxan monohydrate (40-60 mg/kg iv) over 1 min. The global changes in cardiac gene expression in dogs with alloxan-induced diabetes were studied using Affymetrix Canine Array. Cardiac RNA was extracted from the control and DM (n = 4).ResultsThe array data revealed that 797 genes were differentially expressed (P < 0.01; fold change of at least ±2). 150 genes were expressed at significantly greater levels in diabetic dogs and 647 were significantly reduced. There was no change in eNOS mRNA. There was up regulation of some components of the NADPH oxidase subunits (gp91 by 2.2 fold, P < 0.03), and down-regulation of SOD1 (3 fold, P < 0.001) and decrease (4 - 40 fold) in a large number of genes encoding mitochondrial enzymes. In addition, there was down-regulation of Ca2+ cycling genes (ryanodine receptor; SERCA2 Calcium ATPase), structural proteins (actin alpha). Of particular interests are genes involved in glutathione metabolism (glutathione peroxidase 1, glutathione reductase and glutathione S-transferase), which were markedly down regulated.Conclusionour findings suggest that type I diabetes might have a direct effect on the heart by impairing NO bioavailability through oxidative stress and perhaps lipid peroxidases.

【 授权许可】

CC BY   
© Ojaimi et al; licensee BioMed Central Ltd. 2010