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Exosomes have been considered as novel and potent vehicles of intercellular communication, instead of "cell dust". Exosomes are consistent with anucleate cells, and organelles with lipid bilayer consisting of the proteins and abundant lipid, enhancing their "rigidity" and "flexibility". Neighboring cells or distant cells are capable of exchanging genetic or metabolic information via exosomes binding to recipient cell and releasing bioactive molecules, such as lipids, proteins, and nucleic acids. Of note, exosomes exert the remarkable effects on lipid metabolism, including the synthesis, transportation and degradation of the lipid. The disorder of lipid metabolism mediated by exosomes leads to the occurrence and progression of diseases, such as atherosclerosis, cancer, non-alcoholic fatty liver disease (NAFLD), obesity and Alzheimer's diseases and so on. More importantly, lipid metabolism can also affect the production and secretion of exosomes, as well as interactions with the recipient cells. Therefore, exosomes may be applied as effective targets for diagnosis and treatment of diseases. Video abstract [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is characterized by lipids metabolism disorder and inflammatory response. Accumulating evidence has demonstrated that Wingless type 5a (Wnt5a) is implicated in cardiovascular diseases through non-canonical Wnt cascades. However, its precise role during the pathogenesis of AS is still unclear. Therefore, the present study aims to investigate the role and the underlying mechanism of Wnt5a/receptor tyrosine kinase-like orphan receptor 2 (Ror2) pathways in the promotion of AS process through affecting lipid accumulation and inflammation. In atherosclerotic clinical samples, Wnt5a levels were measured by using enzyme-linked immunosorbent assay (ELISA) assay. In vivo experiments were conducted by using apolipoprotein E knockout (apoE−/−) mice model. Vascular smooth muscle cells (VSMCs) were applied for in vitro studies. Wnt5a was highly expressed in both of atherosclerotic clinical samples and apoE−/− mice. The knockdown of Wnt5a significantly inhibited cholesterol accumulation and inflammatory response. Additionally, the lipopolysaccharide (LPS)-induced inflammation aggravated the cholesterol accumulation and decreased adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) expression in VSMCs. Depletion of intracellular cholesterol by β-cyclodextrin (β-CD) led to the upregulation of ABCA1 and the inhibition of inflammation. Conversely, the overexpression of Wnt5a inhibited ABCA1 expression, facilitated cholesterol accumulation, impared cholesterol efflux, promoted NF-κB nuclear translocation and the inflammatory cytokines secretion. Moreover, the knockdown of Ror2 increased ABCA1 expression and reduced Wnt5a-induced cholesterol accumulation and inflammatory responses. Furthermore, the knockdown of ABCA1 enhanced cholesterol accumulation and inflammatory response. Therefore, Wnt5a/Ror2 pathway was critical in regulating cholesterol homeostasis and inflammatory response, which might be a promising therapeutic target for AS therapy. Unlabelled Image • A close correlation between the cholesterol disorder and inflammatory response. • Wnt5a/Ror2 pathway is critical in cholesterol homeostasis and inflammatory response. • ABCA1 involved in Wnt5a/Ror2 axis-mediated cholesterol homeostasis and inflammation. [ABSTRACT FROM AUTHOR]

Vascular remodelling refers to abnormal changes in the structure and function of blood vessel walls caused by injury, and is the main pathological basis of cardiovascular diseases such as atherosclerosis, hypertension, and pulmonary hypertension. Among them, the neointimal hyperplasia caused by abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a key role in the pathogenesis of vascular remodelling. Perivascular adipose tissue (PVAT) can release vasoactive substances to target VSMCs and regulate the pathological process of vascular remodelling. Specifically, PVAT can promote the conversion of VSMCs phenotype from contraction to synthesis by secreting visfatin, leptin, and resistin, and participate in the development of vascular remodelling-related diseases. Conversely, it can also inhibit the growth of VSMCs by secreting adiponectin and omentin to prevent neointimal hyperplasia and alleviate vascular remodelling. Therefore, exploring and developing new drugs or other treatments that facilitate the beneficial effects of PVAT on VSMCs is a potential strategy for prevention or treatment of vascular remodelling-related cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Vascular smooth muscle cells (VSMCs) is one of the main intracellular components of the blood vessel wall. The abnormalities of VSMCs participate in the development of cardiovascular diseases such as atherosclerosis, hypertension, and restenosis, especially the formation and stability of atherosclerotic plaques. Autophagy is involved in the regulation of proliferation, migration and phenotype switching of VSMCs, which in turn affects the pathological process of atherosclerosis. However, the autophagy of VSMCs has a dual effect on cells survival. Autophagy is induced in VSMCs by various stimuli such as 7-ketocholesterol (7-KC), unsaturated lipid peroxidation-derived aldehyde and excess free cholesterol, thereby promoting VSMCs survival and stabilising atherosclerotic plaque. Conversely, autophagy caused by factors such as osteopontin (OPN), angiotensin II (Ang II) and nicotine can accelerate the death of VSMCs, further accelerating atherosclerotic lesions. In addition, mitophagy and lipophagy as selective autophagy are also involved in the outcome of VSMCs as well as progression of atherosclerotic lesion. Currently, there are only a few drugs available to induce VSMCs autophagy, such as atorvastatin, telmisartan and so on. Due to the important role of VSMCs autophagy in the progression of atherosclerosis plaques, drugs that directly target autophagy of VSMCs are urgently needed to be developed. [ABSTRACT FROM AUTHOR]

Angiopoietin-like protein 3 (ANGPTL3) belongs to a multifunctional secreted protein that mainly expresses in the liver, and is regulated by numerous post-translational modifications, including multiple cleavage and glycosylation. Accumulating evidences have revealed that ANGPTL3 plays a critical role in both biological processes, such as lipid metabolism, angiogenesis and haematopoietic function and pathological changes, including atherosclerosis, carcinogenesis, nephrotic syndrome, diabetes, liver diseases and so on. Thus, ANGPTL3 may serve as a potential biomarker in these diseases. Furthermore, ANGPTL3 signalling pathways including LXR/ANGPTL3, thyroid hormone/ANGPTL3, insulin/ANGPTL3 and leptin/ANGPTL3 are also involved in physiological and pathological processes. Some biological ANGPTL3 inhibitors, chemical drugs and traditional Chinese medicine exert beneficial effects by targeting ANGPTL3 directly or indirectly. Therefore, elucidating the effects and underlying mechanisms of ANGPTL3 is essential to develop promising strategies in the diagnosis and treatment of related diseases. [ABSTRACT FROM AUTHOR]

Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, effectively reduces plasma cholesterol, but its effect on atherosclerosis is unclear. Foam cell formation has been implicated as a key mediator during the development of atherosclerosis. The purpose of this study was to investigate the effects of ezetimibe on foam cell formation and explore the underlying mechanism. The results presented here show that ezetimibe reduces atherosclerotic lesions in apolipoprotein E deficient (apoE-/-) mice by lowering cholesterol levels. Treatment of macrophages with Chol:M β CD resulted in foam cell formation, which was concentration-dependently inhibited by the presence of ezetimibe. Mechanically, ezetimibe treatment downregulated the expression of CD36 and scavenger receptor class B1 ( SR-B1), but upregulated the expression of apoE and caveolin-1 in macrophage-derived foam cells, which kept consistent with our microarray results. Moreover, treatment with ezetimibe abrogated the increase of phospho-extracellular signal regulated kinase ( ERK) 1/2 and their nuclear accumulation in foam cells. Inhibition of the MAPK pathway by the MEK inhibitor PD98059 attenuated the inhibitory effect of ezetimibe on the expression of p- ERK1/2 and caveolin-1. Taken together, these results showed that ezetimibe suppressed foam cell formation via the caveolin-1/ MAPK signalling pathway, suggesting that inhibition of foam cell formation might be a novel mechanism underlying the anti-atherosclerotic effect of ezetimibe. [ABSTRACT FROM AUTHOR]

Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are involved in the inflammatory process during atherogenesis. Here, we performed daily gavage of ezetimibe in apolipoprotein E-deficient mice fed with a high-fat diet and found that ezetimibe administration decreased the level of C-reactive protein significantly. To investigate the potential molecular mechanism, we employed microarray analysis on the cultured macrophages treated with Chol:MβCD in the presence or absence of ezetimibe. We found that ezetimibe dramatically down-regulated the expression of the tumor necrosis factor-α (TNF-α) gene. Consistent with the microarray results, TNF-α protein levels were inhibited by ezetimibe. Moreover, ezetimibe suppressed the promoter activity of TNF-α but not TNF-α lacking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) binding domain in THP-1 cells treated with phorbol myristate acetate and Chol:MβCD. Furthermore, treatment of THP-1 macrophages with ezetimibe resulted in the degradation of IκB and subsequently inhibited nuclear translocation of NF-κB and its transcriptional activity. Inhibition of the mitogen-activated protein kinase (MAPK) pathway using PD98059 attenuated the reduction effect of ezetimibe on the expression of NF-κB. Collectively, our results demonstrated that the anti-inflammatory properties of ezetimibe in THP-1 macrophages are, at least in part, through suppression of NF-κB activation via the MAPK pathway. These data provide direct evidence for the potential application of ezetimibe in the prevention and treatment of inflammatory diseases. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]