Stimulation of Vascular Smooth Muscle Cell Proliferation and Migration by Apolipoprotein(a) Is Dependent on Inhibition of Transforming Growth Factor-β Activation and on the Presence of Kringle IV Type 9

Caroline H O'Neil,Michael B Boffa,Mark A Hancock,J Geoffrey Pickering,Marlys L Koschinsky

doi:10.1074/jbc.m409860200

Caroline H O'Neil, Michael B Boffa + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m409860200

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Abstract

Elevated plasma concentrations of lipoprotein(a) are a risk factor for the development of a variety of atherosclerotic disorders. Despite intensive study, the mechanisms by which lipoprotein(a) promotes these disorders remain to be unequivocally defined. It has been demonstrated that lipoprotein(a), through its unique constituent apolipoprotein(a) (apo(a)), stimulates vascular smooth muscle cell (SMC) migration and proliferation. These effects arise from the ability of apo(a) to inhibit the formation of active transforming growth factor beta (TGF-beta) from its latent precursor, which in turn is caused by the ability of apo(a) to decrease the formation of plasmin from its precursor plasminogen. We utilized a battery of recombinant apo(a) variants that represent systematic deletions of the various domains in the molecule to further probe the mechanism underlying the effect of apo(a) on SMC responses. All recombinant apo(a) variants that contained kringle IV type 9 were able to stimulate SMC proliferation and migration and to decrease the formation of active TGF-beta; conversely all recombinant apo(a) variants lacking kringle IV type 9 had no effect on these parameters. The kringle IV type 9-dependent effects of apo(a) on SMC proliferation required the presence of plasminogen, suggesting for the first time that this kringle mediates the ability of apo(a) to inhibit pericellular plasmin formation.

Highlights

Elevated plasma concentrations of lipoprotein(a) (Lp(a))1 constitute an emerging risk factor for the development of a variety of atherosclerotic and thrombotic disorders [1, 2]
These effects arise from the ability of apo(a) to inhibit the formation of active transforming growth factor ␤ (TGF-␤) from its latent precursor, which in turn is caused by the ability of apo(a) to decrease the formation of plasmin from its precursor plasminogen
The kringle IV type 9-dependent effects of apo(a) on smooth muscle cell (SMC) proliferation required the presence of plasminogen, suggesting for the first time that this kringle mediates the ability of apo(a) to inhibit pericellular plasmin formation

Summary

The abbreviations used are

Lp(a), lipoprotein(a); apo(a), apolipoprotein(a); r-apo(a), recombinant apo(a); FCS, fetal calf serum; KIV, kringle IV; SMC, smooth muscle cell; TGF, transforming growth factor. An effect of Lp(a) that may be of particular significance to atherosclerotic disorders is the ability of this lipoprotein, through its apo(a) moiety, to inhibit the formation of active transforming growth factor-␤ (TGF-␤) [15,16,17]. The plasminogen kringle 4-like domains in apo(a) are present in 10 types that differ in amino acid sequence [5]. We utilized a battery of recombinant apo(a) variants in which individual domains are systematically deleted to define the. The apparent requirement of this kringle for inhibition of pericellular plasminogen activation by apo(a) is in contrast to the domain requirements for inhibition by apo(a) of plasminogen activation on fibrin, suggesting different inhibitory paradigms in these two milieus

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION