gw-3965 and Cardiovascular-Diseases

Liver X receptors (LXRs) play an important role in the regulation of cholesterol, fatty acid and glucose metabolisms together with inflammatory processes. In the present study, the effects of LXR agonist GW3965 on vascular reactivity and expression of functional proteins in DOCA-Salt induced hypertension were examined.. Hypertension was induced through unilateral nephrectomy and deoxycorticosterone-acetate (DOCA) injection (20 mg/kg, twice a week) for 6 weeks in male Wistar albino rats (8 weeks old). An LXR agonist GW3965 (10 mg/kg/day, i.p.) was administered to animals for last seven days.. GW3965 treatment reduced systolic blood pressures in hypertensive rats. Acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent vasorelaxations were decreased in hypertensive rats but not affected by GW3965. GW3965 treatment enhanced plasma nitrite levels in normotensive rats. KCl and phenylephrine (Phe)-induced vasocontractions were reduced in hypertensive groups and increased with GW3965 treatment. Decreased sarco/endoplasmic reticulum Ca. The results of study indicate that the LXR agonist, GW3965, exhibited a beneficial effect on increased blood pressure and improved hypertension-induced impairment in contractile activity of vessel and inflammatory markers in vascular tissue. Therefore, these effects of LXR agonists on vessel should be taken into account in experimental or therapeutic approaches to hypertension.

Topics: Animals; Aorta; Benzoates; Benzylamines; Blood Pressure; Cardiovascular Diseases; Desoxycorticosterone Acetate; Disease Models, Animal; Hypertension; Inflammation; Liver X Receptors; Male; Nitroprusside; Rats; Rats, Wistar

Liver X receptor (LXR) activation promotes reverse cholesterol transport (RCT) in rodents but has major side effects (increased triglycerides and LDL-cholesterol levels) in species expressing cholesteryl ester transfer protein (CETP). In the face of dyslipidemia, it remains unclear whether LXR activation stimulates RCT in CETP species. We therefore used a hamster model made dyslipidemic with a 0.3% cholesterol diet and treated with vehicle or LXR agonist GW3965 (30 mg/kg bid) over 10 days. To investigate RCT, radiolabeled (3)H-cholesterol macrophages or (3)H-cholesteryl oleate-HDL were then injected to measure plasma and feces radioactivity over 72 or 48 h, respectively. The cholesterol-enriched diet increased VLDL-triglycerides and total cholesterol levels in all lipoprotein fractions and strongly increased liver lipids. Overall, GW3965 failed to improve both dyslipidemia and liver steatosis. However, after (3)H-cholesterol labeled macrophage injection, GW3965 treatment significantly increased the (3)H-tracer appearance by 30% in plasma over 72 h, while fecal (3)H-cholesterol excretion increased by 156% (P < 0.001). After (3)H-cholesteryl oleate-HDL injection, GW3965 increased HDL-derived cholesterol fecal excretion by 64% (P < 0.01 vs. vehicle), while plasma fractional catabolic rate remained unchanged. Despite no beneficial effect on dyslipidemia, LXR activation promotes macrophage-to-feces RCT in dyslipidemic hamsters. These results emphasize the use of species with a more human-like lipoprotein metabolism for drug profiling.

Topics: Animals; Benzoates; Benzylamines; Bile Acids and Salts; Biological Transport; Cardiovascular Diseases; Cell Line; Cholesterol; Cricetinae; Disease Models, Animal; Dyslipidemias; Fatty Liver; Feces; Gene Expression Regulation; Intestinal Absorption; Lipid Metabolism; Lipoproteins; Lipoproteins, HDL; Liver; Liver X Receptors; Macrophages; Mesocricetus; Mice; Orphan Nuclear Receptors; RNA, Messenger; Time Factors