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Abstract: Objective: Scavenger receptor-class B type I (SR-BI), the receptor for HDL-cholesterol, plays a key role in HDL metabolism, whole body cholesterol homeostasis, and reverse cholesterol transport. We investigated the in vivo impact of hepatic SR-BI inhibition on lipoprotein metabolism and the development of atherosclerosis employing RNA interference. Methods: Small hairpin RNA plasmid specific for rabbit SR-BI was complexed with galactosylated poly-l-lysine, allowing an organ-selective, receptor-mediated gene transfer. Rabbits were fed a cholesterol-rich diet, and were injected with plasmid-complexes once a week. Results: After 2 weeks of treatment hepatic SR-BI mRNA levels were reduced by 80% accompanied by reduced SR-BI protein levels and a modulation of the lipoprotein profile. Rabbits treated with SR-BI-specific plasmid-complexes displayed higher cholesteryl ester transfer from HDL to apoB-containing lipoproteins, lower HDL-cholesterol, and higher VLDL-cholesterol levels, when compared to controls. In a long-term study, this gene therapeutic intervention led to a similar modulation of the lipoprotein profile, to lower total cholesterol levels, and most importantly to a 50% reduction of the relative atherosclerotic lesion area. Conclusion: Our results are another indication that the role of SR-BI in lipoprotein metabolism and atherogenesis in rabbits – a CETP-expressing animal model displaying a manlike lipoprotein profile may be different from the one found in rodents. [Copyright &y& Elsevier]

Abstract: Selective thyromimetics are synthetic analogs of thyroid hormones with tissue-specific thyroid hormone actions. Tissue selectivity is partly mediated by selectivity for the thyroid hormone receptor-β isoform, but is also enhanced by tissue-selective uptake. Several preclinical animal models and recent human clinical trials have provided sound evidence that thyromimetics can serve as pharmacological tools to improve serum lipids without affecting heart rate. Thyromimetics consistently and efficiently lowered low-density lipoprotein cholesterol and lipoprotein (a) plasma levels without positive chronotropic effects. Most importantly, thyromimetics had a synergistic action when used in addition to 3-hydroxy-3-methylglutaryl CoA reductase inhibitors. Animal data have further suggested that thyromimetics might be useful in the treatment of obesity, hepatic steatosis and atherosclerosis. However, only long-term phase III clinical trials will tell if the observed lipid lowering effects of thyromimetics will improve cardiovascular outcome in humans, too. At the moment, the treatment of dyslipidemia seems to be the major indication for the therapeutic use of thyromimetics, which are now rapidly moving from bench to bed-side. [Copyright &y& Elsevier]

Abstract: Objective: Cholesteryl ester transfer protein (CETP) plays a central role in the metabolism of high-density lipoprotein particles. Therefore, we searched for new drugs that bind to CETP and modulate its activity. Methods: A preliminary pharmacophore-based parallel screening approach indicated that leoligin, a major lignan of Edelweiss (Leontopodium alpinum Cass.), might bind to CETP. Therefore we incubated leoligin ex vivo at different concentrations with human (n =20) and rabbit plasma (n =3), and quantified the CETP activity by fluorimeter. Probucol served as positive control. Furthermore, we dosed CETP transgenic mice with leoligin and vehicle control by oral gavage for 7 days and measured subsequently the in vivo modulation of CETP activity (n =5 for each treatment group). Results: In vitro, leoligin significantly activated CETP in human plasma at 100pM (p =0.023) and 1nM (p =0.042), respectively, whereas leoligin concentrations of 1mM inhibited CETP activity (p =0.012). The observed CETP activation was not species specific, as it was similar in magnitude for rabbit CETP. In vivo, there was also a higher CETP activity after oral dosage of CETP transgenic mice with leoligin (p =0.015). There was no short-term toxicity apparent in mice treated with leoligin. Conclusion: CETP agonism by leoligin appears to be safe and effective, and may prove to be a useful modality to alter high-density lipoprotein metabolism. [Copyright &y& Elsevier]

Abstract: Objective: Phospholipid transfer protein (PLTP) facilitates cholesterol efflux from cells, intravascular HDL remodelling and transfer of vitamin E and endotoxin. In humans, the relationship of PLTP to atherosclerosis is unknown. However, strong coronary risk factors like obesity, diabetes, cigarette smoking and inflammation increase circulating levels of active PLTP. The aim of the present, cross-sectional study was to analyze the relationship of PLTP to peripheral arterial disease, a marker of generalized atherosclerosis, independently of potentially confounding factors like obesity, diabetes and smoking. Methods: We performed a case control study in 153 patients with symptomatic peripheral arterial disease (PAD) and 208 controls free of vascular disease. Smokers and patients with diabetes mellitus were excluded. A lipoprotein-independent assay was used for measurement of circulating bioactive PLTP and an ELISA utilizing a monoclonal antibody was used to analyze PLTP mass. Results: PLTP activity was significantly decreased in patients with PAD 5.5 (4.6–6.4)(median (25th–75th percentile)) versus 5.9 (5.1–6.9)μmol/mL/h in controls (p =0.001). In contrast, PLTP mass was similar in patients with PAD 8.5μg/mL (7.3–9.5) and in controls 8.3μg/mL (6.9–9.7) (p =0.665). Multivariate logistic regression analysis revealed that PLTP activity is independently associated with the presence of PAD. PLTP activity was similar in patients with and without lipid-lowering drugs (p =0.396). Conclusion: Our results show that in non-diabetic, non-smoking subjects low rather than high PLTP activity is a marker for the presence of peripheral arterial disease and that distribution of PLTP between high-activity and low-activity forms may be compromised in atherosclerosis. [Copyright &y& Elsevier]