GW3965 hydrochloride is an agonist for the liver X receptor (LXR), reduces angiotensin II-mediated pressor responses in Sprague-Dawley rats. GW3965 acts as a full agonist of hLXRα and hLXRβ (EC50 values are 190 and 30 nM respectively) in cell-based reporter gene assays. It is orally active in mice. When screened against a panel of nuclear receptors, it cross-reacted with only the pregnane X receptor (PXR). GW3965 hydrochloride displays potent antiatherogenic activity in mouse models of atherosclerosis. GW3965 dosing blunted the vasopressor effect of Ang II, which was significantly different with the 0.3 and 3 microg kg(-1) doses. GW3965 decreased Ang II-mediated vasopressor responses coincident with a trend toward reduced ATR gene expression, suggesting that LXR agonists could affect vascular reactivity. Alternate studies suggest that GW3965 hydrochloride increases apoA-I protein levels in the central nervous system independent of ABCA1. Since ABCA1 is a major regulator of cholesterol and phospholipid metabolism, GW3965 hydrochloride is a useful tool to study these cellular functions.
|Cell lines||RAW264.7 cells|
|Preparation method||Cellular Internalization of LXR Agonist
RAW264.7 cells were seeded into 24-well plates at a density of 1 × 105 cells per well 24 hours prior to the experiment. NPs encapsulating a GW3965 concentration of 1 μM were then incubated with cells for the desired time points. Afterwards, the cells were washed with PBS, followed by trypsinization and centrifugation to remove excess trypsin-EDTA. Cells were then resuspended in PBS, and cellular uptake of NPs was assessed via flow cytometry (BD LSR II, BD Bioscience, San Jose, CA). Data were analyzed using BD FACSDiva software.
|Incubation time||2 h|
|Animal models||atherosclerotic lesions in Ldlr−/− mice|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥90 mg/mL|
|Source||Allergol Int (2015). Figure 2. GW3965|
|Incubation Time||1 h|
|Results||We examined the effects of GW3965 on the IgEþAg- or LPS-induced protein expression of IL- 1a, IL-1b, IL-6, and TNF-a. Consistent with our microarray data, GW3965 significantly attenuated the protein expression of IL-1a and IL-1b, but not of IL-6 or TNF-a, in MCs stimulated by IgEþAg|
Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis.
Zhang XQ, et al. Adv Healthc Mater. 2015 Jan 28;4(2):228-36. PMID: 25156796.
The LXR agonist GW3965 increases apoA-I protein levels in the central nervous system independent of ABCA1.
Stukas S, et al. Biochim Biophys Acta. 2012 Mar;1821(3):536-46. PMID: 21889608.
GW3965, a synthetic liver X receptor (LXR) agonist, reduces angiotensin II-mediated pressor responses in Sprague-Dawley rats.
Leik CE, et al. Br J Pharmacol. 2007 Jun;151(4):450-6. PMID: 17420776.
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