Effects of authentic and VLDL hydrolysis-derived fatty acids on vascular smooth muscle cell growth

1 There are contradictory findings regarding the effects of free fatty acid s on vascular smooth muscle cell (VSMC) growth. In the present study we inv estigated the effects of fatty acids released from hydrolysis of human VLDL triglycerides by lipoprotein lipase and of the fatty acids most abundant i n the hydrolysed VLDL, namely oleic, linoleic, palmitic and myristic acid, all non albumin-bound, on VSMC growth. 2 The effect of fatty acids on VSMC growth was assessed by [H-3]-thymidine incorporation, colourimetrically, by cell counting, by determination of the cytoplasmic histone-associated DNA fragments and the caspase 3 activity. T he fatty acid concentrations were determined by gas chromatography-mass spe ctrometry. Stimulation of ERK1/2 and p38 was,determined by the chemilumines cence Western blotting method. 3 Incubation of VSMC with purified VLDL (100 mug ml(-1)) and lipoprotein li pase (35 u ml(-1)) led to almost complete cell death although the ERK1/2 an d the p38 MAP kinases were stimulated. The EC50 of oleic, linoleic, myristi c and palmitic acid were 4.6 +/- 1.3, 2.4 +/- 0.2, 116 +/- 10 and 287 +/- 3 0 muM, respectively. The estimated EC50 of myristic and palmitic acid when derived from hydrolysed VLDL were 10 and 8 times, respectively, lower than when used alone. Apoptosis was not involved in the fatty acid-induced VSMC growth suppression/death. 4 We conclude that (a) non albumin-bound fatty acids cause VSMC necrosis in a dose-dependent manner with a parallel ERK1/2 and p38 stimulation, (b) un saturated fatty acids are more toxic to VSMC than saturated, and (c) satura ted fatty acids are more toxic to VSMC in the hydrolysed VLDL than when use d individually.