Subendothelial proteoglycan synthesis and transforming growth factor beta distribution correlate with susceptibility to atherosclerosis.

Abstract

Coronary bypass vessels, saphenous vein (SV) and internal thoracic artery (ITA), differ in susceptibility to atherosclerosis and medium- to long-term patency. Whereas most ITA remain patent (90% at 10 years), 20% of SV grafts fail in the first year and approximately 45% fail within 10 years. Reasons for these differences are not fully understood. Loss of SV patency may reflect early metabolic events, particularly increased proteoglycan (PG) synthesis which contributes to intimal volume and promotes atherogenesis through retention of atherogenic lipoproteins. We determined, in vitro, the PG metabolic activity of SV, ITA, and human coronary arteries through autoradiographic detection of incorporated [3H]glucosamine. SV had significantly higher levels of PG synthesis than ITA, especially in the subendothelial zone and after time (7 days) in culture. Patterns of synthesis in coronary vessels were similar to SV with high levels of incorporation in the subendothelial zone of thickened intima (> 100 microm). Increased subendothelial labelling in SV was due to increased PG synthesis, not decreased degradation. ITA showed no propensity for upregulation of subendothelial PG synthesis. Immunohistochemistry showed TGF-beta1 and TGF-beta2 localised primarily to the subendothelial zone of SV and coronary arteries. With time in culture immunostaining increased in parallel with increased PG synthesis. Subendothelial TGF-beta1 and TGF-beta2 were absent in ITA. A panspecific TGF-beta neutralising antibody reduced subendothelial PG synthesis in SV and coronary arteries by 50 and 60%, respectively. These results support the idea that vessels susceptible to atherosclerosis show increased accumulation of subendothelial PG mediated by TGF-beta.