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Oxidant-NO dependent gene regulation in dogs with type I diabetes: impact on cardiac function and metabolism
Caroline Ojaimi1, Shintaro Kinugawa, Fabio A Recchia
1Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. caroline_ojaimi@nymc.edu
Insights
Type 1 diabetes impairs heart function by reducing nitric oxide (NO) bioavailability. This study reveals significant changes in cardiac gene expression, including decreased mitochondrial enzymes and glutathione metabolism genes in diabetic dogs.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Diabetes Research
Background:
- Cardiovascular mortality in type 1 diabetes (DM) mechanisms are not fully understood.
- Previous studies showed decreased coronary blood flow and impaired vasodilation in diabetic dogs.
- Reduced nitric oxide (NO) bioactivity from vascular endothelium is a likely cause.
Purpose of the Study:
- Investigate cardiac gene expression changes in a canine model of alloxan-induced type 1 diabetes.
- Identify molecular mechanisms underlying cardiovascular complications in diabetes.
Main Methods:
- Utilized a canine model of alloxan-induced type 1 diabetes.
- Employed Affymetrix Canine Array for global cardiac gene expression analysis.
- Compared gene expression profiles between control and diabetic dogs (n=4).
Main Results:
- 797 differentially expressed genes identified (P < 0.01, fold change ±2).
- Significant downregulation of mitochondrial enzymes (4-40 fold), Ca2+ cycling genes, and glutathione metabolism genes.
- Upregulation of NADPH oxidase subunits (gp91) and downregulation of SOD1 observed.
Conclusions:
- Type 1 diabetes directly impacts the heart by impairing NO bioavailability.
- Oxidative stress and lipid peroxidations likely contribute to these cardiac changes.
- Altered gene expression profiles highlight molecular pathways affected by diabetes in the heart.
Background:
The 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.
Methods:
Mongrel 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).
Results:
The 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.
Conclusion:
our 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.
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