Fatty Acids Cause Alterations of Human Arterial Smooth Muscle Cell Proteoglycans That Increase the Affinity for Low-Density Lipoprotein

Abstract

Objective-The dyslipidemia of insulin resistance, with high levels of albumin-bound fatty acids, is a strong cardiovascular disease risk. Human arterial smooth muscle cell (hASMC) matrix proteoglycans (PGs) contribute to the retention of apoB lipoproteins in the intima, a possible key step in atherogenesis. We investigated the effects of high NEFA levels on the PGs secreted by hASMCs and whether these effects might alter the PG affinity for low-density lipoprotein. Methods and Results-hASMC exposed for 72 hours to high concentrations (800 mol/L) of linoleate (LO) or palmitate upregulated the core protein mRNAs of the major PGs, as measured by quantitative PCR. Insulin (1 nmol/L) and the PPAR␥ agonist rosiglitazone (10 mol/L) blocked these effects. In addition, high LO increased the mRNA levels of enzymes required for glycosaminoglycan (GAG) synthesis. Exposure to NEFA increased the chondroitin sulfate:heparan sulfate ratio and the negative charge of the PGs. Because of these changes, the GAGs secreted by LO-treated cells had a higher affinity for human low-density lipoprotein than GAGs from control cells. Insulin and rosiglitazone inhibited this increase in affinity. Key Words: proteoglycans Ⅲ smooth muscle cells Ⅲ LDL Ⅲ fatty acids Ⅲ insulin I nsulin resistance (IR) and type 2 diabetes (T2D) are associated with a 2-to 4-fold increase in atherosclerotic coronary artery disease. 1,2 Changes in circulating lipoproteins, chronic high levels of albumin-bound nonesterified fatty acids (NEFA, and hyperinsulinemia are important contributors to this association. [3][4][5] Atherogenesis involves a tissue response to deposition of apoB lipoproteins and insulin signaling defects that may affect vascular cells. 6 The accelerated intimal thickening of large arteries observed in IR and diabetes includes excessive production of matrix components, such as proteoglycans (PGs) and collagens by smooth muscle cells (SMCs). 7 Cell culture experiments suggest that increased endothelial cell permeability and SMC alterations of matrix production could be caused by exposure to excessive amounts of NEFA. 8 -10 In IR, arterial cells are chronically exposed to increased levels of circulating NEFA. In addition, NEFA could be produced locally by lipolytic degradation of lipoproteins, additionally increasing their concentration in the arterial intima. 11,12 Retention of low-density lipoprotein (LDL) in the intima by chondroitin sulfate (CS)-rich PGs appears to be a key step in atherogenesis at sites of intima thickening. [13][14][15] We reported that the expression of genes for extracellular matrix proteins and PGs is increased when human arterial SMCs (hASMCs) are exposed to NEFA. Furthermore, the extracellular matrix produced by the NEFA-treated hASMC had a higher affinity for LDL. 9 In this study we describe how linoleate (LO) and palmitate (PA) increased the expression of genes encoding the core proteins of the main secreted PGs from hASMC and of the key enzymes in CS-glycosaminoglycan (GAG) biosynthesis. Exposure to LO also altered...

Proteoglycan mediated lipoprotein retention: A mechanism of diabetic atherosclerosis

“…We found that only TGF-β, which is known to be elevated in subject with diabetes [45][46][47], ND Not determined; GAG glycosaminoglycan chain altered proteoglycan synthesis and LDL binding affinity, but that there was no effect of glucose, insulin or fatty acids [48]. 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].…”

Wogonin ameliorates lipotoxicity-induced apoptosis of cultured vascular smooth muscle cells via interfering with DAG-PKC pathway

“…The most abundant saturated fatty acid in the plasma is palmitate. Studies have indicated that palmitate is involved in atherogenesis by increasing the extent of plaque formation (or plaque score) [36] and inducing extracellular matrix alterations [37] . In this study, we found that the administration of palmitate induced VSMC apoptosis (Figure 2).…”

Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis

“…4,95,96 Biosynthesis can be regulated by a number of factors, including transforming growth factor-␤, platelet-derived growth factor, oxidized LDL, and fatty acids. 4,108,109 Therefore, drugs could alter proteoglycan synthesis either directly or by affecting a regulatory factor. If such manipulation resulted in decreased synthesis of the most highly retentive proteoglycans, lipoprotein retention and ensuing atherogenesis could be suppressed.…”