No abstract

No abstract

SUMMARY: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 g/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 g/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. (Lab Invest 2001, 81:757-765).A therosclerosis is the end stage of a complex interaction of several types of vascular wall resident and infiltrating cells, lipoproteins, and a variety of inflammatory mediators (Daugherty, 1997;Libby et al, 1997;Steinberg and Witztum, 1990). Recently, substantial evidence has accumulated indicating that proinflammatory and immunologic factors play an important role in atherogenesis (Hajjar and Pomerantz 1992;Hansson et al, 1989;Nilsson, 1993;Wick et al, 1995Wick et al, , 1997. It was found that acute phase markedly influences the structure of lipoproteins (Malle et al, 1993;Pruzanski et al, 1998Pruzanski et al, , 2000 and their functions (Kisilevsky and Subrahmanyan, 1992;Shephard et al, 1987;Van Lenten et al, 1995). In acute phase (Baumann and ...

No abstract

These results imply that sPLA2 IIA, which is known to be present in the arterial wall in the vicinity of VSMC, as well as products of lipid hydrolysis induced by sPLA2, enhance the migration of VSMC, and thus may contribute to atherogenic process.