Diabetes mellitus is a major risk factor for developing coronary artery disease. In the diabetic population atherosclerosis accounts for 80% of all deaths compared to one third in the general population. Numerous studies have addressed the complex pathogenesis of coronary artery disease. It is assumed that distinct stages can be defined in the progression of the disease. These contain the monocyte and endothelium mediated oxidation of LDL (oxLDL), the monocyte recruitment and extravasation, the formation of foam cells most likely mediated through scavenger receptors followed by inflammatory responses that lead to the building of atherosclerotic plaques, which potentially rupture and lead to myocardial infarction/ischemia.
In a diabetic environment certain mechanisms exist which are incriminated to promote the formation of atherosclerotic lesions. 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. First of all PKC activation increases the pro-oxidant environment by increasing the production of reactive oxygen species in the endothelium  supporting the formation of oxLDL. Next the endocytosis of oxLDL can be mediated by scavenger receptors that are controlled by PKC . This oxLDL leads to the release of granulocyte-macrophage-colony-stimulating-factors (GM-CSF) which can be blocked by general PKC blockage . Other factors beside the GM-CSF-release contribute for the monocyte adhesion like the expression of P-selectin that is upregulated by PKC activation . Adhesion of monocytes and accumulation of oxLDL results in the formation of cholesterol loaded foam cells and characteristic atherosclerotic lesions. Typical for the development of more complex lesions is the proliferation and migration of vascular smooth muscle cells (VSMCs) in the subendothelial space which is influenced by different isozymes of PKC . Furthermore the expression of different metallomatrix-proteinases (MMPs), which play a crucial role for the plaque stability and the process of plaque rupture , are affected by PKC. So the central role of PKC in all steps of the formation of atherosclerotic plaques is reflected broadly. In addition, functional examinations show a differential pattern of endothelial barrier properties and therefore the permeability of the endothelium depending on the activation of PKC .
PKC is a family of at least twelve isozymes and the particular involvement of the different isozymes is only poorly understood. The family of PKC isozymes is divided in subgroups in order of their enzymatic qualities: The conventional PKCs (cPKC) consist of the isozymes α, β and γ, which are activated in the function of calcium and diacylglycerol (DAG). The new PKCs (nPKC) include the isozymesε, η, δ, andθ, which are activated independently of calcium but in dependence of DAG. The atypical PKCs (aPKC) τ and ζ are activated independently of calcium and DAG. However, the role of PKCs in several important biological processes remains to be elucidated.
In a hyperglycaemic state not only hyperglycaemia per se, but also excessive neurohumoral stimulation are held responsible for the activation of the PKC isozymes [8, 9]. In cardiac tissue, many of these neurohumoral peptides like angiotensin II, endothelin-1 or noradrenalin, which promote vasoconstriction and oxidative stress, bind to receptors that are coupled to the Gq-protein Gα11. Interestingly the blockage of the renin-angiotensin-system (RAS) revealed a significant benefit in controlled randomised studies in a diabetic population [10, 11]. These clinical observations are supported by animal models in which the blockage of the RAS showed a significantly diminished progression of atherosclerosis [12, 13].
Based on these results we generated the hypothesis that a signalling pathway involving the Gq-protein Gα11 may substantially mediate the pattern of PKC isoform expression in diabetes and therefore potentially atherogenesis.
To gain further insight in the complex pathological pathways, the present study analyzed the role of Gα11 on levels of expression of specific PKC isozymes distribution in the coronary vessels in an early diabetic environment.