Lack Of Nogo-B Enhances Atherosclerotic Plaque Stability Via Regulating Smooth Muscle Cell Proliferation And Foam Cell Formation

Atherosclerosis is a chronic inflammatory disease caused by abnormal smooth muscle cells（SMC）proliferation and migration,macrophage lipid deposition,and extracellular matrix accumulation.Nogo-B has been demonstrated multiple pathophysiological functions,such as inhibiting the proliferation and migration of SMC or promoting the adhesion and inflammation of macrophages.However,it remains unknown if Nogo-B can influence the development of atherosclerosis.In this study,we initially observed increased plasma Nogo-B levels in patients with atherosclerosis,and Nogo-B was negatively correlated to ApoE4 in plasma,implying Nogo-B might be involved in the development of atherosclerosis.Therefore,we generated ApoE or LDLR and Nogo dual deficient(ApoE^-/-Nogo^-/-,LDLR^-/-Nogo^-/-)mice.In mice,although it slightly increased lesions,Nogo-B deficiency potently increased the plaque stability in both ApoE^-/-and LDLR^-/-mice by increasing collagen content and fibrous cap areas,while decreasing lipid accumulation,necrotic cores and apoptosis within lesions.Nogo-B deficiency reduced formation of macrophage/foam cells by activating LXR-ABCA1/G1 pathway,while it activated SM22αand SMA expression but reducing matrix metalloproteinases expression to enhance proliferation of pro-contractile SMC.Furthermore,in ApoE^-/-mice,Nogo-B deficiency ameliorated dyslipidemia by activating LDLR expression and cholesterol catabolism through activation of bile acid metabolism in the liver.In LDLR^-/-mice,Nogo-B deficiency demonstrated potent anti-inflammatory functions by activating ApoE production.Taken together,our study demonstrates that Nogo-B deficiency enhanced plaque stability by regulating SMC proliferation,formation of macrophage/foam cells,cholesterol metabolism and inflammation in pro-atherogenic mice.Our study also suggests that Nogo-B might be a promising therapeutic target for patients with vulnerable plaques.