Objective-The development of a murine model of spontaneous atherosclerotic plaque rupture with luminal thrombus. Methods and Results-Combined partial ligation of the left renal artery and left common carotid artery in 8-week-old apolipoprotein E-deficient mice induced endogenous renovascular hypertension and local low oscillatory shear stress in the left common carotid artery. After 8 weeks, a fresh left common carotid artery lumen thrombus associated with severe plaque burden was found in 50% (10/20) of the mice. Histological analyses indicated that all left common carotid artery lesions had vulnerable features, and 50% (5/10) of the mice showed plaque rupture with a lumen thrombus. Multiple layers with layering discontinuity and intraplaque hemorrhages were found in 80% (8/10) of the mice. Further experiments showed that both increased blood pressure, and angiotensin-II contributed to plaque progression and vulnerability. Decreased intimal collagen associated with increased collagenase activity and matrix metalloproteinase expression also resulted in plaque disruption. Conclusion-We demonstrate a murine model of spontaneous plaque rupture with a high incidence of luminal thrombus.The model not only nicely recapitulates the pathophysiological processes of human plaque rupture but it is also simple, fast, and highly efficient to generate. Therefore, in this study, using the method of partial ligation of left carotid and left renal arteries, we induced local stress change, as well as continuously activated reninangiotensin system in ApoE knockout mice. High incidence of spontaneous plaque rupture associated with lumen thrombosis was successfully generated by combining systematic and local factors. Furthermore, this simple murine model not only nicely recapitulates the pathophysiological processes of human plaque rupture but also has rapid plaque progression. Materials and Methods MiceApoE-deficient (ApoE −/− ) mice on a C57BL/6 background were obtained from the Jackson Laboratory (Bar Harbor, ME). Age-(8-week-old) and sex-matched animals weighing between 20 and 25 g were enrolled in the study. Mice batch 1 was randomly assigned to 5 groups: combined partial ligation of left renal artery and left common carotid artery (LCCA) (R+C), partial ligation of left renal artery (R), partial ligation of LCCA (C), sham control (S), and open control (O). Mice batch 2 was also randomly assigned to 5 groups: combined partial ligation of left renal artery and LCCA + intragastrically administered normal saline (R+C+NS), combined partial ligation of left renal artery and LCCA + intragastrically administered losartan (R+C+LO), partial ligation of LCCA + subcutaneous normal saline infusion (C+NS), partial ligation of LCCA + subcutaneous angiotensin II infusion (C+ANG), and partial ligation of LCCA + subcutaneous phenylephrine infusion (C+PHE). For time series experiment, mice were randomly assigned to 4 groups: sham operation was performed in mice of group 1; mice of other groups underwent partial ligation both of LCCA and left ren...

It is well documented that statins protect atherosclerotic patients from inflammatory changes and plaque instability in coronary arteries. However, the underlying mechanisms are not fully understood. Using a previously established mouse model for vulnerable atherosclerotic plaque, we investigated the effect of atorvastatin (10 mg/kg/day) on plaque morphology. Atorvastatin did not lower plasma total cholesterol levels or affect plaque progression at this dosage; however, vulnerable plaque numbers were significantly reduced in the atorvastatin-treated group compared to control. Detailed examinations revealed that atorvastatin significantly decreased macrophage infiltration and subendothelial lipid deposition, reduced intimal collagen content, and elevated collagenase activity and expression of matrix metalloproteinases (MMPs). Because vascular inflammation is largely driven by changes in monocyte/macrophage numbers in the vessel wall, we speculated that the anti-inflammatory effect of atorvastatin may partially result from decreased monocyte recruitment to the endothelium. Further experiments showed that atorvastatin downregulated expression of the chemokines monocyte chemoattractant protein (MCP)-1, chemokine (C-X3-C motif) ligand 1 (CX3CL1) and their receptors CCR2 and, CX3CR1, which are mainly responsible for monocyte recruitment. In addition, levels of the plasma inflammatory markers C-reactive protein (CRP) and tumor necrosis factor (TNF)-α were also significantly decrease in atorvastatin-treated mice. Collectively, our results demonstrate that atorvastatin can improve plaque stability in mice independent of plasma cholesterol levels. Given the profound inhibition of macrophage infiltration into atherosclerotic plaques, we propose that statins may partly exert protective effects by modulating levels of chemokines and their receptors. These findings elucidate yet another atheroprotective mechanism of statins.

Background and Purpose Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor‐α (RXRα) is an intriguing anti‐atherosclerosis target. This study investigated whether and how an RXRα modulator, K‐80003, derived from a non‐steroidal anti‐inflammatory drug attenuates atherosclerotic plaque progression and destabilization. Experimental Approach Our previously established ApoE−/− mouse model of carotid vulnerable plaque progression was treated with K‐80003 or vehicle for 4 or 8 weeks. Samples of carotid arteries and serum were collected to determine atherosclerotic lesion size, histological features, expression of related proteins, and lipid profiles. In vitro studies were carried out in 7‐ketocholesterol (7‐KC)‐stimulated macrophages treated with or without K‐80003. Key Results K‐80003 significantly reduced lesion size, plaque rupture, macrophage infiltration, and inflammatory cytokine levels. Plaque macrophages positive for nuclear p65 (RelA) NF‐κB subunit were markedly reduced after K‐80003 treatment. Also, K‐80003 treatment inhibited 7‐KC‐induced p65 nuclear translocation, IκBα degradation, and transcription of NF‐κB target genes. In addition, K‐80003 inhibited NF‐κB pathway mainly through the reduction of p62/sequestosome 1 (SQSTM1), probably due to promotion of autophagic flux by K‐80003. Mechanistically, cytoplasmic localization of RXRα was associated with decreased autophagic flux. Increasing cytoplasmic RXRα expression by overexpression of RXRα/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K‐80003 strongly inhibited 7‐KC‐induced RXRα cytoplasmic translocation. Conclusions and Implications K‐80003 suppressed atherosclerotic plaque progression and destabilization by promoting macrophage autophagic flux and consequently inhibited the p62/SQSTM1‐mediated NF‐κB proinflammatory pathway. Thus, targeting RXRα‐mediated autophagy‐inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis.

Background: The aim of this study was to assess the preventive effect of xuezhikang (XZK) to replace atorvastatin on the contrast media-induced acute kidney injury (CI-AKI). Methods: The male Sprague-Dawley rats were divided into five groups: group 1 (sham), injected with normal saline; group 2 (XZK), treated with XZK; group 3 contrast media (CM), injected with CM; group 4 (CM þ ATO), injected with CM þ pretreatment with atorvastatin; group 5 (CM þ XZK), injected with CM þ pretreatment with XZK. Twenty-four hours after injection with normal saline or CM, the blood sample and the kidneys were collected for the measurement of biochemical parameters, oxidative stress markers, nitric oxide production, inflammatory parameters, as well as renal histopathology and apoptosis detection. Results: Our results indicated that XZK restored the renal function by reducing serum blood urea nitrogen (BUN) and serum creatinine (Scr), depressing renal malondialdehyde (MDA), increasing renal NO production, decreasing TNF-A and IL-6 expression, attenuating renal pathological changes and inhibiting the apoptosis of renal tubular cells. Conclusion: XZK's therapeutic effect is similar, or even better than atorvastatin at the same effectual dose in some parts.

BackgroundNur77 is an orphan nuclear receptor expressed in human atheroma. In vascular cells in vitro, Nur77 expression is induced by pro-inflammatory factors, such as oxidized LDL (oxLDL).MethodsWe analyze the role of Nur77 in the oxLDL-induced differentiation of macrophages into dendritic cells (DC). The murine RAW264.7 macrophage cell line was stably transfected with expression plasmids encoding either GFP or GFP fusions with either full-length Nur77 (GFP-Nur77), Nur77 lacking the DNA binding domain (GFP-Nur77-ΔDBD) or Nur77 lacking the transactivation domain (GFP-Nur77-ΔTAD).ResultsGFP-Nur77 overexpression significantly suppressed the effect of oxLDL treatment on DC morphologic changes, expression of DC maturation markers, endocytic activity, allogeneic activation of T cell proliferation, and the activity and secretion of pro-inflammatory cytokines. Analysis of GFP-Nur77-ΔTAD and GFP-Nur77-ΔDBD indicated that the Nur77 DNA binding and transactivation domains were both required for this effect. GFP-Nur77-ΔDBD consistently had the opposite effect to GFP-Nur77, increasing DC-type differentiation in all assays. Interestingly, GFP-Nur77-ΔDBD protein was cytosolic, whereas GFP-Nur77 and GFP-Nur77-ΔTAD were both nuclear.ConclusionsThese data show that GFP-Nur77 inhibited differentiation of oxLDL-treated macrophages into DC. The effects of Nur77 on the macrophage phenotype may involve changes in its subcellular distribution.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-014-0054-z) contains supplementary material, which is available to authorized users.