NEFAs have many cellular actions which could impact cardiovascular pathobiology. Although this review focuses principally on the cardiovascular system, NEFAs also have cellular actions implicated in cancer (57-59). Because obese patients are not only at a greater risk for cardiovascular disease but also for cancers of the colon, breast, uterus, and prostate (60-62), NEFAs may be one of the factors contributing to these seemingly disparate observations.
Among the cellular actions of NEFAs are included effects on membrane fluidity and ion transport, e.g., Na+/K+-ATPase, Na+ and K+ channels, and Ca2+ currents (63). The effects of these ion channels on cell function are protean. As examples of potential biological relevance, the capacity of selected cis-unsaturated NEFAs including oleic acid to blunt basal and stimulated release of growth hormone from pituitary cells and nitric oxide from endothelial cells is mediated by inhibitory effects on Ca2+ signaling (22,64). Growth hormone and endothelial function are altered in obesity and may reflect in disordered part NEFA metabolism.
NEFAs enhanced a^adrenoceptor-mediated vascular reactivity through a cyclo-oxygenase sensitive mechanism (32). In cultured vascular smooth muscle cells (VSMCs), oleic and linoleic acids induced a rise of 6-keto-PGF^, a stable metabolite of prostacyclin (65). Although prostacyclin is a vasodilator, a precursor, endoperoxide (PGH2) is an agonist at the thromboxane A2 receptor, which promotes vascular smooth muscle contraction and growth. In these experiments, the mechanism underlying the rise of eicosanoids appeared to be a protein kinase C (PKC)-independent activation of phospholipase A2 (PLA2). Similarly, cis-unsaturated fatty acids including oleic acid facilitated neurotransmission in the hippocampus by a PLA2 signaling pathway (66).
In Raji cells, oleic acid induced cell proliferation (67). In these cells, oleic and arachidonic acids independently affected the expression of genes for cytokines, transcription factors and proteins for cell cycle, defense and repair as well as apoptosis, DNA synthesis, cell adhesion, cytoskeleton, and hormone receptors. The greatest effects of the fatty acids occurred on the genes coding for signal transduction proteins. Although the mechanisms by which NEFAs affect transcription are not fully known, some genes appear to have an oleate response element in the promoter region (68). NEFAs activate peroxisome proliferators-activated receptors and NF-kB, which function as nuclear transcriptional regulators (24,69). NEFAs also induce a PKC-dependent increase in mitogen activated/extracellular-regulated protein kinase (MEK) (70), which have downstream effects on nuclear transcription (71).
Cis-unsaturated NEFAs, including oleic and linoleic acids, can directly activate the typical and atypical isoforms of PKC by a diacylglycerol (DAG)-independent mechanism (72,73). Selected NEFAs bind to the regulatory domain of PKC at a site separate from that of DAG. NEFAs, in general, appear to be full agonists for the Ca2+-independent and atypical PKC isoforms and partial agonists for the Ca2+-independent isoforms (74). The EC50 for activation of PKC for selective isoforms is within the range of estimated intracellular concentrations, which raises the possibility that cis-unsaturated NEFAs are biologically relevant regulators of cell signaling processes.
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