Abstract
BackgroundDiabetes mellitus counts as a major risk factor for developing atherosclerosis. The activation of protein kinase C (PKC) is commonly known to take a pivotal part in the pathogenesis of atherosclerosis, though the influence of specific PKC isozymes remains unclear. There is evidence from large clinical trials suggesting excessive neurohumoral stimulation, amongst other pathways leading to PKC activation, as a central mechanism in the pathogenesis of diabetic heart disease. The present study was therefore designed to determine the role of Gq-protein signalling via Gα11 in diabetes for the expression of PKC isozymes in the coronary vessels.MethodsThe role of Gα11 in diabetes was examined in knockout mice with global deletion of Gα11 compared to wildtype controls. An experimental type 1-diabetes was induced in both groups by injection of streptozotocin. Expression and localization of the PKC isozymes α, βII, δ, ε, and ζ was examined by quantitative immunohistochemistry.Results8 weeks after induction of diabetes a diminished expression of PKC ε was observed in wildtype animals. This alteration was not seen in Gα11 knockout animals, however, these mice showed a diminished expression of PKCζ. Direct comparison of wildtype and knockout control animals revealed a diminished expression of PKC δ and ε in Gα11 knockout animals.ConclusionThe present study shows that expression of the nPKCs δ and ε in coronary vessels is under control of the g-protein Gα11. The reduced expression of PKC ζ that we observed in coronary arteries from Gα11-knockout mice compared to wildtype controls upon induction of diabetes could reduce apoptosis and promote plaque stability. These findings suggest a mechanism that may in part underlie the therapeutic benefit of RAS inhibition on cardiovascular endpoints in diabetic patients.
Highlights
Diabetes mellitus counts as a major risk factor for developing atherosclerosis
Coronary protein kinase C (PKC) expression in wildtype and Ga11 knockout animals under normoglycaemic conditions To evaluate the influence of the g-protein Ga11 on the coronary expression of the PKC isoforms a, bII, δ, ε and ζ, which are known to take crucial part in the pathogenesis of atherosclerosis, we compared wildtype control animals (WT) and Ga11 knockout control animals (KO) (Figure 1)
The atypical PKC isoform ζ (PKCζ; WT: 180.48 ± 99.75; KO: 253.11 ± 38.45; p = 0.48) in turn was expressed in the coronary vessels of wildtype and Ga11 knockout animals (Figure 2C vs. Figure 3C)
Summary
Diabetes mellitus counts as a major risk factor for developing atherosclerosis. The activation of protein kinase C (PKC) is commonly known to take a pivotal part in the pathogenesis of atherosclerosis, though the influence of specific PKC isozymes remains unclear. The building of advanced glycation end products (AGEs) which is mainly determined by the level of glucose and time of exposure, the induction of hyperglycaemia induced oxidative stress, hyperglycaemia mediated inflammation through cytokines including activation of monocytes and adipocytes, the activation of the hexosamine pathway and the regulation of proteinkinase C (PKC) activity are interacting and engaging in the pathogenesis of atherosclerosis as described above. Numerous operations of these demonstrate a participation of PKC activation. Functional examinations show a differential pattern of endothelial barrier properties and the permeability of the endothelium depending on the activation of PKC [7]
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