The Effects Of Liver X Receptor On Vulnerable Plaques And Underlying Mechanisms

Objective:Liver X receptor(LXR)belongs to the metabolic nuclear receptor superfamily,which plays a critical regulatory role in vascular physiology/pathology.However,the effects of systemic LXR activation on established vulnerable plaques remain unclear.Here,we aimed to clarify whether LXR has a protective role in rupture-prone plaque progression and endoplasmic reticulum(ER)stress-related macrophage dysfunction.Methods and Results:After carotid branch ligation and renal artery constriction,8-week-old male Apo E^-/-mice were randomly assigned to three groups(Baseline,Vehicle,and GW3965,n=6,respectively)and fed a high-fat diet during the rest experiment procedure.Plaques in the left carotid artery acquired vulnerable features 4 weeks later,confirmed by MRI scans and histological analysis.At this time,mice were injected intraperitoneally daily with PBS or GW3965(10 mg/kg per day)for an additional 4 weeks.Treatment with LXR agonists alleviated arterial outward remodeling,and lesion volume was reduced by 52.61%,compared with the Vehicle group(65.62±2.34 versus 31.10±2.56*10⁷?m³,p<0.0001).Importantly,a profile of less intraplaque hemorrhage detection and necrotic core formation was found(19.76±2.31 versus 6.58±0.79%of lesion area,p<0.0001;28.64±2.41 versus 12.37±1.71%of lesion area,p<0.0001).These actions collectively attenuated the incidence of plaque rupture(5/6 versus 1/6,p=0.0833).Mechanistically,reduced in situ apoptosis and aberrant ER stress as well as enhanced efferocytosis are involved.In concert with benefits on vulnerable plaques,preincubation of cultured macrophages with LXR agonists before 7-Ketocholesterol stimulation inhibited ER stress.Furthermore,the ER-protective effects of LXR agonists were lost in the setting of genetic ablation of LXR?,but not LXR?isotype.Conclusion:Our results revealed that activation of LXR has the potential to stabilize vulnerable plaques and prevent plaque rupture via amelioration of macrophage ER stress,the associated apoptosis,and defective efferocytosis,these findings will expand the application scenarios of LXR therapeutics for atherosclerosis.