Vascular Dysfunction: Free Fatty Acids and Vascular Damage

Background. Elevated plasma concentrations of free fatty acids (FFAs) are an important component of diabetes- associated dyslipidemia and contribute to endothelial dysfunction. The latter represents an early stage of diabetic angiopathy (retinopathy, accelerated atherosclerosis), characterized by accelerated apoptosis of human vascular cells. We recently demonstrated induction of endothelial apoptosis by elevated plasma FFAs and different nutritional FFAs. Signaling pathways of these effects, however, remain to be elucidated. Potential effects of plasma free fatty acids and isolated nutritional FFAs in other types of vascular cells (pericytes, smooth muscle cells - HSMCs) remain to be evaluated. Aims. This proposal aims to analyze i) direct effects of elevated plasma FFAs, of different nutritional FFAs (saturated, mono-/polyunsaturated, 3/6/9) and of oxidized FFAs on vascular cell apoptosis, proliferation, and related protein expression, ii) cell type dependence(micro-/macrovascular endothelial cells, vascular smooth muscle cells and retinal pericytes) of these effects, and iii) to characterize the respective underlying signaling pathways and target molecules, e.g. c-myc, PPAR, NF-B, protein kinases (Akt, PKC, MAPK). Preliminary experiments. High plasma-FFA concentrations (as seen after Intralipid infusion) induce apoptosis in HSMCs compared with an intraindividual low plasma-FFA control (before Intralipid infusion). HSMCs and endothelial cells show, however, a completely different response to selected nutritional FFAs: Oleic acid significantly triggers apoptosis in smooth muscle cells, but not in endothelial cells, whereas saturated stearic acid induces endothelial apoptosis, but hardly smooth muscle cell death. Western blots and functional studies suggest different signaling pathways to be involved in FFA action, depending on both FFAs` structure and cell type. Clinical relevance. Characterization of nutritional FFAs` effects and signaling pathways in vascular cells isolated from target tissues of late diabetic vascular complications could help to develop therapeutic strategies preventing or ameliorating diabetes-associated vascular damage. Such strategies could include pharmacological intervention as well as recommendation of a vasoprotective diet using the respective nutritional fatty acids.