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.

Effect of TGF-β₁ Antisense S-Oligonucleotide on Synthesis and Accumulation of Matrix Proteoglycans in Balloon Catheter-Injured Neointima of Rabbit Carotid Arteries

“…In human coronary arteries, TGF-β 1 shows strong immunostaining in the subendothelial zone of thickened intimas [2], while TGF-β 1 expression is increased in vessels following balloon injury [7]and is elevated in human restenotic lesions [8]. The distribution of TGF-β 1 correlates strongly with PG levels.…”

“…The distribution of TGF-β 1 correlates strongly with PG levels. In human coronary arteries, the synthesis of PG is significantly elevated in the TGF-β 1 -rich subendothelial intimal zone (the proteoglycan layer of Stary [18]), and this raised level of synthesis can be significantly abrogated by TGF-β-neutralising antibody [2]. …”

“…In excess amounts, however, particularly in thickened primary and restenotic intima, they may increase tissue volume and be atherogenic through a number of mechanisms [1]. In vessels susceptible to atherosclerosis, the PG species versican and biglycan are particularly prominent in the subendothelial zone of thickened intima, and that distribution correlates closely with the distribution patterns for transforming growth factor-β 1 (TGF-β 1 ) [2]. TGF-β 1 is a potent stimulator for PG synthesised by vascular smooth muscle cells (SMC) [3, 4, 5, 6].…”

Proteoglycan mediated lipoprotein retention: A mechanism of diabetic atherosclerosis

“…However, other groups have reported that fatty acid stimulation of vascular smooth muscle cells alters proteoglycan synthesis [49,50]. The finding that TGF-β stimulation of vascular smooth muscle cell increases proteoglycan synthesis and proteoglycan-LDL binding is robust [51][52][53][54][55].…”

Angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the increase in TGF-β1 in thyroid hormone-induced cardiac hypertrophy

“…It is well known that ANG II upregulates TGF-β1 expression via activation of the AT1 receptor in cardiomyocytes and fibroblasts, and induction of this peptide is an absolute requirement for ANG II-induced cardiac hypertrophy in vivo [19]. In contrast, a previous study demonstrated that, in valvular interstitial cells, the AT2 receptor blocker was able to attenuate the ANG IIstimulated TGF-β1 secretion, demonstrating that in some types of cells, the AT2 receptor is also able to modulate TGF-β1 [25]. Accordingly, our findings corroborate with the fact that both ANG II receptors are involved in modulation of cardiac TGF-β1, also in cardiac hypo and hyperthyroidism models.…”