POLYUNSATURATED FATTY-ACIDS AND SIGNALING VIA PHOSPHOLIPASE C-BETA AND A(2) IN MYOCARDIUM

Dietary n-6 and n-3 polyunsaturated fatty acids (PUFAs) have potent bi ological effects on the blood(cells), the vasculature and the myocardi um. In the epidemiological studies in which the benefit from the regul ar ingestion of n-3 PUFAs was reported, the responsible mechanisms rem ain obscure. A great deal of the PUFA-effect can be explained by the k nown interference with the eicosanoid metabolism. Many processes, beli eved to be involved in atherogenesis such as adhesion and infiltration of bloodcells (in)to the vasculature, platelet aggregation, secretion of endothelium-derived factors and mitogenic responses of vascular sm ooth muscle cells are partially mediated by receptor-activated phospho lipases C-beta and A(2). As PUFAs take part at many steps of the signa lling pathways, the latter could represent important action sites to b eneficially interfere with atherogenesis. In this brief review, we hav e discussed the results of studies on the influence of alteration of P UFA composition of the membrane phospholipids or of exogenously admini stered non-esterified PUFAs on phospholipid signalling. For convenienc e, we have mainly focused our discussion on those studies available on the myocardium. By changing the PUFA composition of the phospholipids , the endogenous substrates for the membrane-associated phospholipase C-beta and A(2) are changed. This is accompanied by changes in their h ydrolytic action on these substrates resulting in altered products (th e molecular species of 1,2-diacylglycerols and the non-esterified PUFA s) which on their turn evoke changes in events downstream of the signa lling cascades: activation of distinct protein kinase C isoenzymes, fo rmation of distinct eicosanoids and non-esterified PUFA effects on Ca2 + channels. It has also become more clear that the membrane physicoche mical properties, in terms of fluidity and cholesterol content of the bilayer, might undergo changes due to altered PUFA incorporation into the membrane phospholipids. The latter effects could have consequences for the receptor functioning, receptor-GTP-binding protein coupling, GTP-binding protein-phospholipase C-beta or A(2) coupling as well. It should be noted that most of these studies have been carried out with cardiomyocytes isolated from hearts of animals on PUFA diet or incubat ion of cultured cardiomyocytes with non-esterified PUFAs in the presen ce of albumin. Studies need to be performed to prove that the PUFA-die t induced modulations of the phospholipid signalling reactions do occu r in vivo and that these effects are involved in the mechanism of bene ficial effects of dietary PUFAs on the process of atherosclerosis.