LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms

Abstract

The aim of this study was to define the antiatherosclerotic role of liver-X-receptors (LXRs) under lesion progressive and lesion regressive conditions, to establish a temporal line of events, and to gain insights into the mechanisms underlying the anti-atherogenic potency of LXRs. We used apoE*3Leiden (E3L) mice to comprehensively and time-dependently dissect how T0901317, an LXR-agonist, inhibits initiation and progression of atherosclerotic lesions and regresses existing lipid-and macrophage-rich lesions. T0901317 suppresses lesion evolution and promotes lesion regression regarding lesion number, area, and severity. Quantitative plasma and vessel wall analyses corroborated by immunohistochemical evaluation of the aortic lesions revealed that under progressive (high-cholesterol diet) as well as regressive (cholesterol-free diet) conditions T0901317: i) significantly increases plasma triglyceride and total cholesterol levels; ii) does not affect the systemic inflammation marker, Serum amyloid A (SAA); iii) suppresses endothelial monocyte adhesion; and iv) induces the expression of the cholesterol efflux-related genes apolipoprotein E (apoE), ATP binding cassette (ABC) transporters ABCA1 and ABCG1. Furthermore, under progressive conditions, T0901317 suppresses the vascular inflammatory status (NF-kB) and the vascular expression of adhesion molecules [E-selectin, intercellular adhesion molecule (ICAM)-1, and CD44], lowers lesional macrophage accumulation, and blocks lesion evolution at the transition from lesional stage II to III. Under regressive conditions, T0901317 induces lesional macrophage disappearance and increases the expression of the chemokine receptor CCR7, a factor functionally required for regression. The LXR-agonist T0901317 retards vascular lesion development and promotes lesion regression at several levels.The findings support that vascular LXR is a potential antiatherosclerotic target.-Verschuren, L., J. de Vries-van der Weij, S. Zadelaar, R. Kleemann, and T. Kooistra. LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms. J. Lipid Res. 2009. 50: 301-311.

LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression

“…The present results propose an additional mechanism for LXR-atheroprotection, namely, their stimulation of CD68 + cell emigration from plaques through the induction of Ccr7. LXR-dependent acquisition of CCR7 function in CD68 + plaque cells is also consistent with previous work by us (50) and others (24,48), as well as with the more general finding that the acquisition of migratory ability during differentiation of monocytes to DCs is concomitant with both LXR isoforms being expressed (51, 52).…”

“…Recently, it has also been shown that LXRs also negatively regulate the inflammatory state of macrophages through effects on toll-like receptors and NF-κB (46,47). Activation of LXRs and absence of LXRs have been shown to promote regression (38,48) and exacerbate progression (39,49), respectively, of atherosclerosis in mouse models. These effects of LXRs have been attributed to the aforementioned roles in RCT and inflammation.…”

Interruption of the OX40–OX40 Ligand Pathway in LDL Receptor–Deficient Mice Causes Regression of Atherosclerosis

“…Reintroducing apolipoprotein E (ApoE) into ApoE 2/2 mice via ApoE gene transfer induces regression (3,4). Furthermore, LXR compounds induce atherosclerotic regression by promoting reverse cholesterol transport in macrophages (5). Another approach to study regression was introduced by Feig et al (6) who used a model in which atherosclerosis-containing aortic segments from ApoE 2/2 mice were transplanted into wild-type recipient mice.…”

Macrophages, extracellular matrix, and lipoproteins in arterial cholesterol balance

“…Freeman et al show that the liver X receptor (LXR) agonist TO901317 increases the deposition of cholesterol microdomains in the ECM produced by macrophages. It is known that, besides upregulation of ABCA1 and ABCG1, LXR agonists both in vivo and in vitro upregulate apoE expression ( 8 ). Future colocalization experiments with MAb(s) against the microdomains and against apoE in cell cultures and in human lesions could be informative in this respect.…”