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

Multifactorial interaction among lipoproteins, vascular wall cells, and inflammatory mediators has been recognized as the basis of atherogenesis. In the arterial wall high-density lipoprotein (HDL) and human secretory phospholipase A(2) (sPLA(2)) colocalize with vascular smooth muscle cells and concentrate in the atherosclerotic lesions. It has been shown that gr IIA sPLA(2) hydrolyzes lipoproteins, altering their structure and releasing active agents such as lyso-phosphatidylcholine (PtdCho) and free fatty acids. We investigated the impact of normal HDL(3) (NHDL(3)), acute phase HDL(3) (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 [(3)H] thymidine incorporation by DNA of cultured human vascular smooth muscle cells (VSMC). NHDL(3) markedly enhanced mitogenic activity of VSMC in a dose- and time-dependent manner. Doubling of thymidine incorporation was usually achieved by 40 microg/ml of NHDL(3) after 4 hours of incubation. APHDL(3) had invariably a stronger inducing effect on the mitogenic activity than NHDL(3); 40 microg/ml more than tripled [(3)H] thymidine incorporation after 4 hours of incubation. NHDL(3) preincubated with human apo serum amyloid A apolipoprotein-induced higher mitogenic activity in VSMC than NHDL(3) alone. Hydrolysis of NHDL(3), APHDL(3), or LDL by gr IIA sPLA(2) markedly enhanced mitogenic activity of VSMC as compared with unhydrolyzed lipoproteins. sPLA(2) concentrations that can be found in atherosclerotic vascular walls markedly enhanced lipoprotein-induced mitogenic activity of VSMC. sPLA(2) per se did 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 such as oleic and linoleic acids and lyso-PtdCho or their combinations with NHDL(3) explains in part markedly enhanced mitogenic activity of VSMC. It is conceivable that sPLA(2,) which is known to colocalize with lipoproteins in the vascular wall in the domain of VSMC, is capable of induction of the mitogenic activity in these cells in vivo and should be considered as a proatherogenic enzyme.