Synergistic Effects of Growth Factors on the Regulation of Smooth Muscle Cell Scavenger Receptor Activity

Abstract

Rabbit smooth muscle cells (SMC) express types I and II scavenger receptors (ScR) that are up-regulated by platelet secretion products. In the current studies we investigated the effect of growth factors secreted by platelets on ScR activity in rabbit and human SMC. Platelet-derived growth factor (PDGF BB) and transforming growth factor ␤ 1 (TGF-␤ 1 ) at 10 ng/ml increased ScR activity in rabbit SMC (by approximately 4-and 2-fold, respectively) but not in human SMC. Epidermal growth factor (EGF) or insulin-like growth factor I (IGF-I) alone had little effect on SMC ScR activity. The growth factors had synergistic effects on ScR activity and on types I and II ScR mRNA expression. In rabbit SMC, PDGF BB, EGF, and TGF-␤ 1 together stimulated ScR activity 12-fold. In human SMC, EGF and TGF-␤ 1 , together with either IGF-I or PDGF BB, stimulated receptor activity approximately 7-fold. Growth factor-mediated induction of ScR activity in rabbit and human SMC was blocked by the tyrosine kinase inhibitor tyrphostin 47, whereas the induction of ScR activity in rabbit but not human SMC was blocked by the protein kinase C inhibitor MDL.29,152. Studies using neutralizing antibodies demonstrated that TGF-␤ 1 is the predominant factor in in vitro preparations of platelet secretory products which regulates ScR activity. The growth factors that act synergistically in regulating ScR activity in vitro are all present in atherosclerotic lesions, where they are produced by macrophages, endothelial cells, SMC, and platelets. The data suggest that these growth factors may regulate ScR activity in SMC in vivo and contribute to foam cell formation.

Tumor Necrosis Factor-α-mediated Protein Kinases in Regulation of Scavenger Receptor and Foam Cell Formation on Macrophage

“…(37,48,74) and in smooth muscle cell (SMC) (46,47,54,55) have been studied. The transcription factor-binding sites for activating protein 1 (AP-1)/ETS between the sequence of Ϫ67 and Ϫ50 bp and region IV in the 5Ј-flanking region of human MSR gene promoter have been identified (37,74).…”

Oxidant stress: the role of nutrients in cell-lipoprotein interactions

“…Recent work carried out with rabbit vascular smooth muscle cells has shown that oxidant stress induced by phorbol esters resulted in an induction of the scavenger receptor (Gong & Pitas, 1995;Mietus-Snyder et al 1997). We have studied the direct effects of free radicals on cellular cholesterol metabolism.…”

Class A Scavenger Receptor Up-regulation in Smooth Muscle Cells by Oxidized Low Density Lipoprotein

“…We have shown, however, that SMC express SR-A and that receptor expression is regulated over a wide range (7)(8)(9)(10). SR-A activity is induced in SMC by treatments that increase intracellular oxidative stress, such as phorbol esters and the combination of H 2 O 2 and vanadate (11).…”

“…SR-A activity is induced in SMC by treatments that increase intracellular oxidative stress, such as phorbol esters and the combination of H 2 O 2 and vanadate (11). Certain growth factors that increase SMC SR-A activity (10) have also been associated with increased oxidative stress, including interleukin-1, tumor necrosis factor ␣ (12), epidermal growth factor (13), platelet-derived growth factor (10,14), and transforming growth factor ␤ (10, 15). The latter two factors are responsible for the up-regulation of SMC SR-A activity by platelet secretory products (10).…”

“…Certain growth factors that increase SMC SR-A activity (10) have also been associated with increased oxidative stress, including interleukin-1, tumor necrosis factor ␣ (12), epidermal growth factor (13), platelet-derived growth factor (10,14), and transforming growth factor ␤ (10, 15). The latter two factors are responsible for the up-regulation of SMC SR-A activity by platelet secretory products (10). Reactive oxygen species (ROS), such as superoxide anions and H 2 O 2 , function as second messengers in signal transduction, mediating ligand stimulation by tyrosine phosphorylation (16).…”