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NOS dependent gene regulation in cardiac tissues of conscious type I diabetic dogs
Author(s) -
Ojaimi Caroline,
Kinugawa Shintaro,
Hintze Thomas H.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1155.9
Subject(s) - medicine , endocrinology , bradykinin , chemistry , apocynin , nadph oxidase , biology , biochemistry , receptor , oxidative stress
We have shown that in conscious dogs with type I diabetes (DM) that baseline CBF was significantlydecreased, endothelium‐dependent (ACh) coronary vasodilation were impaired, and reflex cholinergic NO‐dependent coronary vasodilation was selectivelydepressed. The likely mechanism responsible for the depressedreflex cholinergic NO‐dependent coronary vasodilation was thedecreased bioactivity of NO from the vascular endothelium. Bradykinin reduced oxygen consumption in normal dog heart in vitro (38 ± 1.3%) and this was reduced in type I DM (18 ± 1.6%). The effect of bradykinin was restored by apocynin (30 ± 0.9%), tempol (30 ± 1.1%) or vit C (29 ± 0.7%) indicating a role for NADPH oxidase derived superoxide. Affymetrix Canine Arrays were used to study gene expression in dogs with alloxan‐induced diabetes. Cardiac RNA was extracted from the control and DM (n=4). The data revealed that 797 genes were differentially expressed (P<0.01; fold change of at least ±2). There was no change in eNOS mRNA. There was up regulation of some components of the NADPH oxidase subunits (gp91 (2.2 fold), P<0.03), glutathione peroxidase and down‐regulation of SOD1 (3 fold, P<0.001) and decrease (4–40 fold) in a number of genes encoding mitochondrial enzymes such as cytochrome c oxidase, NADH‐ubiquinone oxidoreductase, ubiquinol‐cytochrome c reductase, ATP synthase, isocitrate dehydrogenase 3, succinate dehydrogenase and aconitase 2. There was down‐regulation of Ca2+ cycling genes (ryanodine receptor; SERCA2 Calcium ATPase), and structural proteins (actin alpha). In conclusion, these data show a direct effect of diabetes on the heart by impairing NO bioavailability through oxidative stress. Supported by HL‐PO1‐43023.