Immunohistochemical analysis of target proteins of Rho-kinase in a mouse model of accelerated atherosclerosis.

Background: The pleiotropic antiatherosclerotic effects of statins are believed to be associated with the inhibition of Rho-kinase. However, a systematic analysis of Rho-kinase activation in atherosclerotic lesions is missing.

Objectives: To analyze the distribution and phosphorylation of target proteins of Rho-kinase, such as myosin light chain (MLC) and ezrin-radixin-moesin (ERM) proteins, in the apolipoprotein E (ApoE) knockout model of accelerated atherosclerosis, as well as the effects of treatment with the Rho-kinase inhibitor Y-27632.

Identification and characterization of hamster stearoyl-CoA desaturase isoforms.

Stearoyl-CoA desaturase (SCD) catalyzes the formation of monounsaturated fatty acids from saturated fatty acids. It plays a key role in lipid metabolism and energy expenditure in mammals. In mice, four SCD isoforms (SCD1-4) have been identified.

Identification of a novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674), that produces marked changes in serum lipids and apolipoprotein A-1 expression.

Low high-density lipoprotein-cholesterol (HDL-c) is an important risk factor of coronary artery disease (CAD). Optimum therapy for raising HDL-c is still not available. Identification of novel HDL-raising agents would produce a major impact on CAD.

Conversion of human-selective PPARalpha agonists to human/mouse dual agonists: a molecular modeling analysis.

To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.

Rosiglitazone treatment improves insulin regulation and dyslipidemia in type 2 diabetic cynomolgus monkeys.

Impairment of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor that regulates genes involved in lipid and glucose metabolism, may contribute to the onset of metabolic disorders such as diabetes and the accompanying dyslipidemia. Fat-derived tumor necrosis factor alpha (TNF-alpha) and the acute-phase response protein, C-reactive protein (CRP), may also have a role in the development of obesity-related insulin resistance and type 2 diabetes mellitus. In this study, a group of 14 naturally occurring, insulin-requiring, type 2 diabetic cynomolgus monkeys were used to evaluate the effects of the PPAR-gamma agonist, rosiglitazone, on glycemic and lipid parameters and serum levels of TNF-alpha and CRP.

Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists.

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.

Coadministration of a liver X receptor agonist and a peroxisome proliferator activator receptor-alpha agonist in Mice: effects of nuclear receptor interplay on high-density lipoprotein and triglyceride metabolism in vivo.

Liver X receptors (LXRs) are master transcription factors regulating cholesterol and fatty acid metabolism. Treatment of C57B6 mice with a specific synthetic LXR agonist, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide (T0901317), resulted in elevated high-density lipoprotein (HDL) cholesterol as well as plasma and liver triglycerides. Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists are known to induce peroxisomal fatty acid beta-oxidation and also mediate HDL cholesterol metabolism.

Design and synthesis of a potent and selective triazolone-based peroxisome proliferator-activated receptor alpha agonist.

A new series of hPPARalpha agonists containing a 2,4-dihydro-3H-1,2,4-triazol-3-one (triazolone) core is described leading to the discovery of 5 (LY518674), a highly potent and selective PPARalpha agonist.

Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice.

Objective: Accompanying more atherogenic lipoprotein profiles and an increased incidence of atherosclerosis, plasma cholesteryl ester transfer protein (CETP) is depressed in diabetic obese patients compared with nondiabetic obese counterparts. The depressed levels of CETP in the plasma of diabetic obese individuals may contribute to the development of an atherogenic lipoprotein profile and atherogenesis. We have examined the effect of CETP expression on vascular health in the db/db model of diabetic obesity.

Phospholipid transfer protein is regulated by liver X receptors in vivo.

Liver X receptors (LXR) belong to the nuclear receptor superfamily that can regulate important lipid metabolic pathways. The plasma phospholipid transfer protein (PLTP) is known to mediate transfer of phospholipids from triglyceride-rich lipoproteins to high density lipoprotein (HDL) and plays a critical role in HDL metabolism. We report here that a specific LXR agonist, T0901317, elevated HDL cholesterol and phospholipid in C57/BL6 mice and generated enlarged HDL particles that were enriched in cholesterol, ApoAI, ApoE, and phospholipid.

Peroxisome proliferator-activated receptor alpha,gamma coagonist LY465608 inhibits macrophage activation and atherosclerosis in apolipoprotein E knockout mice.

The apolipoprotein E (apoE) knockout mouse has provided an approach to the investigation of the effect of both cellular and humoral processes on atherosclerotic lesion progression. In the present study, pharmacologic modulation of both interferon gamma (IFNgamma)-inducible macrophage effector functions, and atherosclerotic lesions in the apoE knockout mouse were investigated using the peroxisome proliferator-activated receptor (PPAR) alpha,gamma coagonist LY465608. LY465608 inhibited, in a concentration-dependent manner, IFNgamma induction of both nitric oxide synthesis and the beta 2 integrin CD11a in elicited peritoneal macrophages from apoE knockout mice.

A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-alpha/gamma agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models.

A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1).