TRANSFORMING-GROWTH-FACTOR-BETA IS SEQUESTERED INTO AN INACTIVE POOL BY LIPOPROTEINS

Elevated plasma concentrations of low density lipoprotein (LDL) and ve ry-low density lipoprotein (VLDL) have been correlated with the develo pment of atherosclerosis. These lipoproteins may promote atherogenesis by direct deposition of lipid in the vessel wall. In addition, precio us data suggested that there was an inverse correlation between serum LDL-cholesterol concentration and tile proportion of transforming grow th factor beta (TGF-beta) in an active form (Grainger et al. 1995. Nat ure Med. 1:74). Here we have investigated whether lipoproteins can aff ect the activity of TGF-beta 1 in plasma and show that TGF-beta can as sociate with the lipoprotein fraction. In the plasma of healthy males, 16 +/- 5% (mean +/- standard deviation; n = 57) of the total plasma T GF-beta 1 was associated dth tile lipoprotein Fraction, dth tile major proportion (64 +/- 15%) in tile HDL-3 subtraction. However, in ten di abetic subjects with moderately poor glucose control (Hb alc > 8.0), d ie proportion of total plasma TGF-beta in the lipoprotein fraction was 68 +/- 21%. This large increase in TGF-beta 1 associated with the lip oprotein fraction was mainly due to association with VLDL, chylomicron s, and LDL. The lipoprotein fraction inhibits TGF-beta 1 binding to th e type II TGF-beta receptor extracellular domain iii an ELISA and inhi bits TGF-beta 1 activity in the mink lung cell bioassay. We propose th at sequestration of TGF-beta into lipoproteins represents a novel mech anism by which TGF-beta activity in circulation may be regulated. Lipo protein sequestration of TGF-beta may therefore contribute to the seve re depression of TGF-beta activity in advanced atherosclerosis.