Mitogenic effect of lipoproteins on human vascular smooth muscle cells: The impact of hydrolysis by gr IIa phospholipase A(2)

Multifactorial interaction among lipoproteins, vascular wall cells, and inf lammatory mediators has been recognized as the basis of atherogenesis. In t he arterial wall high-density lipoprotein (HDL) and human secretory phospho lipase A(2) (sPLA(2)) colocalize with vascular smooth muscle cells and conc entrate in the atherosclerotic lesions. It has been shown that gr IIA sPLA( 2) hydrolyzes lipoproteins, altering their structure and releasing active a gents such as lyso-phosphatidylcholine (PtdCho) and free fatty acids. We in vestigated the impact of normal HDL3 (NHDL3), acute phase HDL3 (APHDL(3)), and low-density lipoprotein (LDL), both unhydrolyzed and sPLA(2)-hydrolyzed , and some products of hydrolysis, such as lyso-PtdCho, oleic and linoleic acid, on [H-3] thymidine incorporation by DNA of cultured human vascular sm ooth muscle cells (VSMC). NHDL3 markedly enhanced mitogenic activity of VSM C in a dose- and time-dependent manner. Doubling of thymidine incorporation was usually achieved by 40 mug/ml of NHDL3 after 4 hours of incubation. AP HDL(3) had invariably a stronger inducing effect on the mitogenic activity than NHDL3; 40 mug/ml more than tripled [3H] thymidine incorporation after 4 hours of incubation. NHDL3 preincubated with human apo serum amyloid A ap olipoprotein-induced higher mitogenic activity in VSMC than NHDL3 alone. Hy drolysis of NHDL3, APHDL(3), or LDL by gr IIA sPLA(2) markedly enhanced mit ogenic activity of VSMC as compared with unhydrolyzed lipoproteins. sPLA(2) concentrations that can be found in atherosclerotic vascular walls markedl y enhanced lipoprotein-induced mitogenic activity of VSMC. sPLA(2) per se d id not affect thymidine incorporation and VSMC did not release sPLA(2) into the medium. There was no evidence for hydrolysis of the wall of VSMC by gr IIA sPLA(2). The presence of the products of hydrolysis of lipoproteins su ch as oleic and linoleic acids and lyso-PtdCho or their combinations with N HDL3 explains in part markedly enhanced mitogenic activity of VSMC. It is c onceivable that sPLA(2) which is known to colocalize with lipoproteins in t he vascular wall in the domain of VSMC, is capable of induction of the mito genic activity in these cells in vivo and should be considered as a proathe rogenic enzyme.