Dose-dependent coronary artery intimal thickening after local delivery of the anti-oxidant tetradecylthioacetic acid from stents.

OBJECTIVE: To examine the in vitro uptake and elution of the anti-oxidant tetradecylthioacetic acid (TTA) from phosphorylcholine (PC)-coated stents, and the in vivo uptake, retention, inflammatory response and histomorphometric changes after overstretch injury of the porcine coronary artery. METHODS: PC-coated stents were loaded in one of three different concentrations of TTA (87, 174 and 347 mmol/L, i.e. 25, 50 and 100 mg/mL) and randomized versus PC-coated stents to the right coronary or left circumflex artery (18 pigs). Uptake of TTA into the coronary wall from the 347 mmol/L concentration was measured after 3 h and 24 h, 7 days, 14 days and 28 days (two pigs at each time point). RESULTS: In vitro, TTA was successfully loaded onto the stents and elution was nearly complete after 48 h. In vivo, TTA could be demonstrated in the vessel wall for up to 4 weeks. Percent area stenosis was significantly higher in the TTA group, 35.2+/-20.9% versus 27.5+/-17.0% (p=0.03). Dose-related comparison showed increased intimal thickness, 0.66+/-0.53 mm versus 0.29+/-0.26 mm (p=0.008) and intimal area, 2.83+/-1.61 mm2 versus 1.58+/-0.91 mm2 (p=0.004) for the 347 mmol/L TTA versus controls. There was a significantly positive relationship between the TTA-loading dose and both intimal area (B=0.69, p=0.01) and maximal intimal thickness (B=0.17, p=0.02). The pro-inflammatory precursor arachidonic acid increased four-fold in the arterial wall of the TTA group, while the anti-inflammatory fatty acid index, calculated as (docosapentaenoic acid+docosahexaenoic acid+dihomo-linolenic acid)/arachidonic acid, was suppressed to 0.65+/-0.27 compared to 1.13+/-0.23 in control vessels (p<0.001). CONCLUSION: TTA caused a dose-dependent intimal thickening and reduced anti-inflammatory fatty acid index. Contrary to expectations, TTA seems unsuitable as stent coating.

Tetradecylselenoacetic acid, a PPAR ligand with antioxidant, antiinflammatory, and hypolipidemic properties.

OBJECTIVE: Antioxidants protect against oxidative stress and inflammation, which, in combination with hyperlipidemia, are important mediators of atherogenesis. Here we present a selenium-substituted fatty acid, tetradecylselenoacetic acid (TSA), which is hypothesized to have antioxidant, antiinflammatory, and hypolipidemic properties. METHODS AND RESULTS: We show that TSA exerts antioxidant properties by delaying the onset of oxidation of human low density lipoprotein (LDL), by reducing the uptake of oxidized LDL in murine macrophages, and by increasing the mRNA level of superoxide dismutase in rat liver. TSA also showed antiinflammatory effects by suppressing the release of interleukin (IL)-2 and -4, and by increasing the release of IL-10 in human blood leukocytes. In addition, TSA decreased the plasma triacylglycerol level and increased the mitochondrial fatty acid beta-oxidation in rat liver. In pigs, TSA seemed to reduce coronary artery intimal thickening after percutaneous coronary intervention. In HepG2 cells TSA activated all peroxisome proliferator-activated receptors (PPARs) in a dose-dependent manner. CONCLUSIONS: Our data suggest that TSA exert potent antioxidant, antiinflammatory, and hypolipidemic properties, potentially involving PPAR-related mechanisms. Based on these effects, it is tempting to hypothesize that TSA could be an interesting antiatherogenic approach to atherosclerotic disorders.

Fish protein hydrolysate reduces plasma total cholesterol, increases the proportion of HDL cholesterol, and lowers acyl-CoA:cholesterol acyltransferase activity in liver of Zucker rats.

There is growing evidence that soy protein improves the blood lipid profiles of animals and humans. We compared the effects of fish protein hydrolysate (FPH), soy protein, and casein (control) on lipid metabolism in Wistar rats and genetically obese Zucker (fa/fa) rats. In Zucker rats, FPH treatment affected the fatty acid composition in liver, plasma, and triacylglycerol-rich lipoproteins. The mRNA levels of Delta 5 and Delta 6 desaturases were reduced by FPH and soy protein feeding compared with casein feeding. In Zucker rats both FPH and soy protein treatment reduced the plasma cholesterol level. Furthermore, the HDL cholesterol:total cholesterol ratio was greater in these rats and in the Wistar rats fed FPH and soy protein compared with those fed casein. Although fecal total bile acids were greater in soy protein-fed Zucker rats than in casein-fed controls, those fed FPH did not differ from the controls. However, the acyl-CoA:cholesterol acyltransferase activity was reduced in Zucker rats fed FPH and tended to be lower (P = 0.13) in those fed soy protein compared with those fed casein. Low ratios of methionine to glycine and lysine to arginine in the FPH and soy protein diets, compared with the casein diet, may be involved in lowering the plasma cholesterol concentration. Our results indicate that the effects of FPH and soy protein on fatty acid metabolism are similar in many respects, but the hypocholesterolemic effects of FPH and soy protein appear to be due to different mechanisms. FPH may have a role as a cardioprotective nutrient.

Inhibition of rat lipoprotein oxidation after tetradecylthioacetic acid feeding.

We have previously shown that tetradecylthioacetic acid (TTA), a sulfur containing saturated fatty acid analogue, inhibits the oxidative modification of human low-density lipoprotein (LDL) in vitro. The oxidative modification of LDL is believed to be a crucial step in the progression of atherosclerosis. In the present study, we investigated the effect of TTA oral administration on the susceptibility of rat lipoprotein to undergo oxidative modification ex vivo. Lipoprotein resistance to copper-induced oxidation was highly improved after TTA administration to rats. Conjugated dienes produced after 150 min of lipoprotein oxidation were dramatically lowered in the TTA treated rats compared to controls. Malondialdehyde and lipid peroxides production by oxidation was highly limited. These effects were independent of any Vitamin E effects. More than 50% relative reduction in polyunsaturated fatty acids of the n-3 family, and more than 30% relative increase in 18:1n-9 fatty acid in the triacylglycerol (TAG)-rich lipoprotein were observed. TAG-rich lipoprotein lipids of TTA fed rats were decreased with more than 50% reduction in TAG. The data reported in this paper indicate a potent in vivo antioxidant capability of TTA that beside its hypolipidemic effect might be of importance in relation to the development of atherosclerosis.