Abstract
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.
Highlights
The mechanisms responsible for the cardiovascular mortality in type I diabetes (DM) have not been defined completely
In another study [12], we have shown that: 1) kallikrein causes a decrease in O2 consumption in cardiac muscle from normal dogs, which is mediated by kinin and nitric oxide (NO) mechanisms; and 2) the modulation of O2 consumption by endogenous NO is depressed in cardiac muscle from diabetic dogs, whereas the modulation of O2 consumption by exogenous NO is still preserved
Recording Techniques Arterial pressure, LV pressure, left circumflex coronary blood flow (CBF), and internal diameters were measured; heart rate (HR), mean arterial pressure, and mean CBF were derived in conscious dogs, as we described previously [11]
Summary
The mechanisms responsible for the cardiovascular mortality in type I diabetes (DM) have not been defined completely. The most likely mechanism responsible for the depressed reflex cholinergic NO-dependent coronary vasodilation was the decreased bioactivity of NO from the vascular endothelium. Due to altered intermediary metabolism in DM, a feature present in both type 1 and type 2 DM, patients with type 2 DM, even in the absence of clinical cardiovascular disease, have a reduced maximal oxygen consumption compared with non-diabetic people [6]. Several studies have reported that the basal metabolic rate is increased in diabetic states [7,8]. This increase is a reflection of the increased metabolic demands in DM
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