Spontaneous Atherothrombosis and Medial Degradation in Apoe ^−/− , Npc1 ^−/− Mice

Abstract

Background-The formation of an occluding thrombus on a ruptured or eroded atherosclerotic plaque is the hallmark event leading to acute coronary syndromes, myocardial infarction, and sudden death in humans. However, other species are highly resistant to plaque complications, and the specific processes predisposing to plaque destabilization and thrombosis are poorly understood. Methods and Results-Mice carrying a null mutation of a gene regulating intracellular cholesterol transport (the Niemann-Pick C1 [Npc1] gene) were crossed with apolipoprotein E (Apoe) knockout mice to examine the effect of Npc1 on atherosclerotic lesion formation. Double-mutant mice showed greater lesion area compared with Apoe Ϫ/Ϫ littermates. Remarkably, the double mutants also developed large, protruding thrombi associated with the plaques and prominent medial degradation with inflammatory cell infiltration into the adventitia. Genetic studies suggested that the BALB background was permissive for plaque complications compared with C57BL/6J, and a BALB susceptibility locus was mapped by linkage analysis to chromosome 6. Examination of clotting parameters in double-knockout mice revealed that native clotting times were shortened and thrombin-antithrombin complex and soluble CD40 ligand levels were elevated compared with wild-type controls. In addition, cathepsin K was induced in Npc1 Ϫ/Ϫ macrophages, and cathepsin K immunostaining and elastase activity were increased in proximal aortas of double-mutant mice compared with controls. Conclusions-A defect in intracellular cholesterol trafficking caused by the Npc1 null mutation predisposes to increased lesion formation, atherothrombosis, and medial degradation. Plaque complications may require a procoagulant state and an increased protease activity, leading to plaque destabilization.

Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking

“…On the other hand, 125 I-VLDL clearance was significantly accelerated in MφNpc1 -/-mice compared with MφNpc1 +/+ mice ( Figure 3C) and was accompanied by a hepatic free cholesterol level 1.8-fold that of MφNpc1 +/+ mice ( Figure 3D Figure 4C). The aortic lesions in both MφNpc1 +/+ and MφNpc1 -/-mice exhibited a high degree of cellularity with extensive macrophage infiltration, in agreement with an earlier report (23), and no changes were observed in the extent of macrophage apoptosis (data not shown). However, MφNpc1 -/-mice did not exhibit the profound atherothrombotic phenotype previously observed in the whole-body Npc1 -/-Apoe -/-mice (23).…”

“…The aortic lesions in both MφNpc1 +/+ and MφNpc1 -/-mice exhibited a high degree of cellularity with extensive macrophage infiltration, in agreement with an earlier report (23), and no changes were observed in the extent of macrophage apoptosis (data not shown). However, MφNpc1 -/-mice did not exhibit the profound atherothrombotic phenotype previously observed in the whole-body Npc1 -/-Apoe -/-mice (23). The discordance between the serum lipoprotein levels and aortic atherosclerosis suggested that intrinsic alterations in macrophage sterol metabolism in the MφNpc1 -/-mice likely play a greater role in atherosclerotic lesion formation than do serum lipoprotein levels.…”

“…A previous study that examined the effect of Npc1 deficiency on atherogenesis did not find differences in aortic lesional area in high-fat diet-fed Npc1 +/-Apoe -/-mice compared with Apoe -/-mice, although NPC1 heterozygosity was associated with resistance to lesional necrosis and lesional macrophage apoptosis (37). More recently, Welch et al reported that introduction of the Npc1 -/-mutation into the Apoe -/-background predisposed to increased lesion formation and atherothrombosis (23). In agreement with these studies, we found that NPC1…”

ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet

“…The slides were counterstained with nuclear fast red. PECAM immunostaining was carried out as previously described (64).…”

Reduced VLDL clearance in ApoeNpc1 mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels

“…Ϫ / Ϫ ) mice fed a chow diet for 12 weeks exhibited accelerated atherosclerosis in proximal aortas as well as an elevation of plasma total cholesterol ( 14 ). We recently found that these mice had increased VLDL levels in a Balb/c genetic background.…”