A comparison of oxidized LDL-induced collagen secretion by graft and aortic SMCs: role of PDGF

Abstract

Smooth muscle cells (SMCs) from prosthetic vascular grafts constitutively secrete higher levels of collagen than aortic SMCs. Lipid oxidation products accumulate in grafts, and we postulated that they stimulate SMC production of collagen. The effect of oxidized low-density lipoprotein (oxLDL) on type I collagen secretion by aortic and graft SMCs was compared. SMCs isolated from the canine thoracic aorta or Dacron thoracoabdominal grafts (n = 10) were incubated with native LDL or oxLDL (0-400 microg cholesterol/ml) for 72 h. Type I collagen in the conditioned medium was measured by ELISA. OxLDL increased collagen production by graft SMCs from 4.1 +/- 0.3 to 11.0 +/- 0.4 ng/microg DNA and by aortic SMCs from 2.3 +/- 0.1 to 3.5 +/- 0.2 ng/microg DNA. Native LDL had little effect. LY-83583, a superoxide generator, stimulated a dramatic increase in collagen secretion by graft SMCs and a smaller but significant elevation by aortic SMCs. OxLDL has been shown to increase PDGF production by graft SMCs, and PDGF can stimulate collagen production. Anti-PDGF antibody inhibited the increase in collagen production by graft SMCs that was stimulated by oxLDL, implicating PDGF as one mechanism of oxLDL-induced collagen production. Lipid oxidation products that accumulate in prosthetic vascular grafts can cause an oxidative stress that stimulates PDGF production by graft SMCs that in turn stimulates collagen production, contributing to the progression of intimal hyperplasia.

ROS-mediated downregulation of MYPT1 in smooth muscle cells: a potential mechanism for the aberrant contractility in atherosclerosis

“…34 LY83583-induced superoxide production, but not H 2 O 2 , increases procollagen a1 (I) mRNA levels in canine aortic smooth muscle cells, which suggests that superoxide anion regulates gene expression. 35 Our results that LY83583 treatment reduced both MYPT1 mRNA and protein levels in HASMCs are consistent with this notion. Furthermore, the attenuation of LY83583-reduced MYPT1 protein levels by the co-treatment with a membranepermeable SOD strongly implicates a role for superoxide anion in MYPT1 reduction.…”

Impaired graft healing due to hypercholesterolemia is prevented by dietary supplementation with α-tocopherol

“…6 Oxidized low-density lipoprotein (oxLDL) also stimulates SMC growth factor production by ECs, 7 is chemotactic for SMCs, 8 stimulates SMC proliferation, 9 and enhances SMC production of collagen. 10 These properties adversely affect vascular graft healing.…”

Factors influencing collagen biosynthesis

“…Nevertheless there is a reported negative effect on human arterial smooth muscle cells [Okada et al, 1993]. The recent study by Absood et al [2004] showed that PDGF caused increased collagen production by synthetic smooth muscle cells but not by contractile smooth muscle cells. The oxLDL induced increase in collagen production was blunted by the addition of anti-PDGF antibody, suggesting that PDGF mediated the stimulation of collagen synthesis.…”

“…In a study conducted by Absood et al [2004], it is reported that oxidized LDL and superoxide generator LY-83583 induce higher level of collagen synthesis in graft and aortic smooth muscle cells. Superoxides are known to stimulate collagen synthesis by hepatocytes and fibroblast in vitro [Hussain et al, 1987;Chandrakasan and Bhatnagar, 1991].…”

“…Superoxides are known to stimulate collagen synthesis by hepatocytes and fibroblast in vitro [Hussain et al, 1987;Chandrakasan and Bhatnagar, 1991]. But hydrogen peroxide does not have a role in collagen synthesis [Absood et al, 2004].…”