共查询到20条相似文献,搜索用时 31 毫秒
1.
Objectives
The aim of the present study was to investigate the effect of urokinase-type plasminogen activator (uPA) on the expression of the scavenger receptor class B type I (SR-BI) in hepatocytes, and its impact on the removal of HDL-cholesteryl ester (CE) in the liver.Methods and results
Huh7 hepatoma cell lines were incubated with increasing concentrations of uPA. uPA dose-dependently decreased SR-BI protein expression, as determined by flow cytometry (FACS) and by Western blot assays, and down-regulated SR-BI gene expression. Functionally, uPA decreased both the cellular binding of HDL to Huh7 hepatocytes, and the selective uptake of CE from HDL, as determined by several methods including BODIPY staining, cellular cholesterol determination and chasing radio-labeled CE transfer from HDL to the cells. These results were further confirmed using primary rat hepatocyes. The effect of uPA on hepatic SR-BI expression was mediated via binding to the uPA receptor (uPAR). In vivo, SR-BI protein and gene expressions were found to be increased in hepatocytes derived from the uPAR-KO mice compared to C57Bl/6 mice, and in parallel HDL-cholesterol levels in plasma derived from uPAR-KO mice were decreased. Moreover, deficiency of uPAR significantly accelerated the plasma decay of injected HDL-[3H]CE.Conclusions
The results of this study suggest that uPA decreases the removal of HDL-CE in the liver via suppression of the hepatic SR-BI expression. Impaired reverse cholesterol transport (RCT) may result in atherogenic dysfunctional HDL metabolism and may contribute to atherosclerosis development. 相似文献2.
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Sophie Colin Mélanie Fanchon Loic Belloy Andrea E. Bochem Corinne Copin Bruno Derudas Erik S.G. Stroes G. Kees Hovingh Jan A. Kuivenhoven Geesje M. Dallinga-Thie Bart Staels Giulia Chinetti-Gbaguidi 《International journal of cardiology》2014
Background
Macrophages are crucial cells in the pathogenesis of atherosclerosis. Macrophages are plastic cells which can switch from a classical pro-inflammatory M1 to an alternative anti-inflammatory M2 macrophage phenotype, depending on the environmental stimuli. Because high-density lipoprotein (HDL) cholesterol levels are inversely correlated to cardiovascular disease and since HDL displays anti-inflammatory properties, we investigated whether HDL can affect alternative macrophage differentiation of primary human monocytes in the presence of interleukin (IL)-4, a M2 macrophage polarization driver, in vitro and ex vivo.Methods and results
M2 macrophages are highly responsive to HDL stimulation, since the expression of pentraxin 3 (PTX3), a well known HDL target gene, is induced by HDL more strongly in M2 macrophages than in control unpolarized resting macrophages (RM). As expected, the expression of M2 markers, such as Mannose Receptor (MR), CD200 Receptor (CD200R), Coagulation factor XIII A1 (F13A1), IL-1 receptor antagonist (IL-1RA) and IL10, was induced in IL-4 polarized M2 macrophages compared to RM. However, incubation with HDL added in vitro did not modulate the gene expression of M2 macrophage polarization markers. Moreover, monocytes isolated from subjects with genetically low HDL levels, carrying ABCA1 or LCAT mutations, differentiated ex vivo into M2 macrophages without any difference in the alternative macrophage marker expression profile.Conclusions
These in vitro and ex vivo results indicate that, contrary to mouse macrophages, HDL does not influence macrophage M2 polarization of human monocyte-derived macrophages. Thus, the anti-inflammatory properties of HDL in humans are probably not related to the enhancement of the M2 macrophage phenotype. 相似文献4.
Chandrakala Aluganti Narasimhulu Krithika SelvarajanMatthew Brown Sampath Parthasarathy 《Atherosclerosis》2014
Objective
Apolipoprotein A1 (ApoA1) and apolipoprotein E (ApoE) mimetic peptides have attracted attention due to their ability to reduce atherosclerosis and exhibit antioxidant, anti-inflammatory, and hypolipidemic properties. In this study, we tested whether three distinct and unrelated cationic peptides would inhibit the oxidation of lipoproteins and whether they would counteract and neutralize the negatively charged modified lipoproteins, inhibit their uptake and inflammation by macrophages.Methods and results
5F-mimetic peptide of ApoA1, LL27 derived from the anti-microbial peptide hCAP, and a human glycodelin derived peptide were commercially synthesized. We noted that these three distinct cationic lysine-rich peptides, two of which were unrelated to any known apolipoproteins, inhibited copper-mediated oxidation of lipoproteins and reduced lipid peroxides in a lysine dependent manner. The peptides also retarded the electrophoretic mobility of previously oxidized LDL and acetylated LDL by virtue of their net positive charge. Pre-incubation of peptides with modified lipoproteins reduced the uptake of the latter by macrophages, thus preventing the formation of foam cells. The cationic peptides inhibited oxidized LDL (Ox-LDL)-induced inflammatory response both in vitro and in vivo.Conclusion
Based on these results, we suggest that in addition to the well known mimetic peptides, other suitable cationic peptides may be of use for controlling Ox-LDL mediated inflammation and atherosclerotic progression. 相似文献5.
Silvia D'Alessio Gabriella Fibbi Marina Cinelli Serena Guiducci Angela Del Rosso Francesca Margheri Simona Serratì Marco Pucci Bashar Kahaleh Pansheng Fan Francesco Annunziato Lorenzo Cosmi Francesco Liotta Marco Matucci‐Cerinic Mario Del Rosso 《Arthritis \u0026amp; Rheumatology》2004,50(10):3275-3285
Objective
Defective angiogenesis, resulting in tissue ischemia, is particularly prominent in the diffuse form of systemic sclerosis (SSc). The present study was undertaken to identify possible differences between normal and SSc microvascular endothelial cells (MVECs) in the expression of the cell‐associated urokinase‐type plasminogen activator (uPA)/uPA receptor (uPAR) system, which is critical in the angiogenic process.Methods
MVECs were isolated from the dermis of healthy individuals and from the dermis of patients with diffuse SSc. The uPA/uPAR system was examined at the protein and messenger RNA levels. Angiogenesis was assayed on Matrigel‐coated porous filters and plates to evaluate cell proliferation, invasion, and capillary morphogenesis. Cleavage of uPAR and the activity of matrix metalloproteinase 12 (MMP‐12) were evaluated by Western blotting.Results
Compared with MVECs from healthy skin, MVECs from SSc patients showed higher expression of uPAR. However, in SSc MVECs, uPAR undergoes truncation between domain 1 and domain 2, as shown by flow cytometry, enzyme‐linked immunosorbent assay, and Western blotting, a cleavage that is known to impair uPAR functions. These properties of SSc MVECs were associated with poor spontaneous and uPA‐dependent invasion, proliferation, and capillary morphogenesis. The uPAR cleavage occurring in SSc MVECs was associated with overexpression of MMP‐12. SSc MVEC–conditioned medium impaired uPA‐dependent proliferation and invasion as well as capillary morphogenesis in normal MVECs in vitro. Both a general hydroxamate inhibitor of MMP activity and anti–MMP‐12 antibodies restored this SSc MVEC–induced impaired functioning.Conclusion
Overproduction of MMP‐12 by SSc MVECs accounts for the cleavage of uPAR and the impairment of angiogenesis in vitro and may contribute to reduced angiogenesis in SSc patients.6.
Jun Li Da-Sheng Zhang Jiang-Chuan Ye Chang-Ming Li Man Qi Dan-Dan Liang Xin-Ran Xu Liang Xu Yi Liu Hong Zhang Yang-Yang Zhang Fang-Fei Deng Jing Feng Dan Shi Jin-Jin Chen Li Li Gang Chen Yun-Fu Sun Lu-Ying Peng Yi-Han Chen 《International journal of cardiology》2013
Background
Heart failure (HF) is approaching an epidemic proportion and has become one of the leading causes of death. It imposes a great burden on the healthcare system and society. Remodeling of cardiomyocyte membranes has a profound role in the pathogenesis of HF. However, whether dynamin (DNM), a membrane-remodeling GTPase, is associated with HF remains unclear.Methods and results
Here, we identified that DNM2 is necessary for the maintenance of cardiac function. Endogenous DNM2 protein levels were gradually decreased in parallel with the progression of HF in different experimental animal models. Decreased DNM2 level was also observed in the end-stage failing human heart. DNM2-deficient zebrafish exhibited signs of notable cardiac apoptosis and eventually developed severe HF. Mechanistic study showed that DNM2 downregulation caused cardiomyocyte sarcoplasmic reticulum Ca2 + overload and subsequent mitochondria-dependent apoptosis. These events were preceded by enhanced membrane translocation of the L-type Ca2 + channel due to DNM2 deficiency-mediated membrane trafficking dysfunction. Furthermore, prevention of cardiomyocyte Ca2 +-mishandling largely ameliorated the DNM2 deficiency-associated cardiomyocyte apoptosis and HF.Conclusions
DNM2 mediates HF by modulating Ca2 +-dependent apoptotic death of cardiomyocyte. The finding may shed light on the new strategy of HF treatment. 相似文献7.
Background
The urokinase-type (uPA) and tissue-type (tPA) plasminogen activators regulate liver matrix remodelling through the conversion of plasminogen (Plg) to the active protease plasmin. Based on the efficient activation of plasminogen when uPA is bound to its receptor (uPAR) and on the role of uPA in plasmin-mediated liver repair, we hypothesized that uPA requires uPAR for efficient liver repair. 相似文献8.
John C. Scatizzi Jack Hutcheson Richard M. Pope Gary S. Firestein Alisa E. Koch Melissa Mavers Avraham Smason Hemant Agrawal G. Kenneth Haines Navdeep S. Chandel Richard S. Hotchkiss Harris Perlman 《Arthritis \u0026amp; Rheumatology》2010,62(2):441-451
Objective
Rheumatoid arthritis (RA) is a destructive autoimmune disease characterized by an increased inflammation in the joint. Therapies that activate the apoptotic cascade may have potential for use in RA; however, few therapeutic agents fit this category. The purpose of this study was to examine the potential of Bim, an agent that mimics the action of Bcl‐2 homology 3 (BH3) domain–only proteins that have shown success in preclinical studies of cancer, in the treatment of autoimmune disease.Methods
Synovial tissues from RA and osteoarthritis patients were analyzed for the expression of Bim and CD68 using immunohistochemistry. Macrophages from Bim−/− mice were examined for their response to lipopolysaccharide (LPS) using flow cytometry, real‐time polymerase chain reaction analysis, enzyme‐linked immunosorbent assay, and immunoblotting. Bim−/− mice were stimulated with thioglycollate or LPS and examined for macrophage activation and cytokine production. Experimental arthritis was induced using the K/BxN serum–transfer model. A mimetic peptide corresponding to the BH3 domain of Bim (TAT‐BH3) was administered as a prophylactic agent and as a therapeutic agent. Edema of the ankles and histopathologic analysis of ankle tissue sections were used to determine the severity of arthritis, its cellular composition, and the degree of apoptosis.Results
The expression of Bim was reduced in RA synovial tissue as compared with controls, particularly in macrophages. Bim−/− macrophages displayed elevated expression of markers of inflammation and secreted more interleukin‐1β following stimulation with LPS or thioglycollate. TAT‐BH3 ameliorated arthritis development, reduced the number of myeloid cells in the joint, and enhanced apoptosis without inducing cytotoxicity.Conclusion
These data demonstrate that BH3 mimetic therapy may have significant potential for the treatment of RA.9.
Objective
Macrophages are key players in atherosclerotic lesion formation and progression. We have recently demonstrated that lipid-loaded macrophages show activation of the canonical Wnt signaling pathway.Methods
To test the in vivo role of the canonical Wnt pathway in atherosclerosis we used mice deficient in the Wnt signaling receptor LRP5 (LRP5−/−) fed a hypercholesterolemic diet (HC) to induce atherosclerosis. These dietary groups were further subdivided into two subgroups receiving their respective diets supplemented with 2% plant sterol esters (PSE). All mice remained on their assigned diets until age 18 weeks.Results
HC WT mice had mildly increased non-HDL cholesterol levels, developed aortic atherosclerotic lesions and showed upregulated expression levels of aortic Lrp5. HC LRP5−/− mice develop larger aortic atherosclerotic lesions than WT mice indicating that LRP5 has a protective function in atherosclerosis progression. The oral administration of PSE, a dietary cholesterol-lowering agent, had an effect in the expression levels of the Wnt signaling receptor and in atherosclerosis progression. We found that PSE reduced serum total cholesterol levels, abolished HC-induced LRP5 overexpression and reduced aortic atherosclerotic plaques.Conclusion
The proatherogenic effects of the excess of plasma lipids are in part mediated by modulation of LRP5 in the aorta. LRP5 and canonical Wnt signaling exert a protective defense mechanism against hyperlipidemia and atherosclerosis lesion progression. 相似文献10.
Yun-Cheng Lv Yan-Yan Tang Juan Peng Guo-Jun Zhao Jing Yang Feng Yao Xin-Ping Ouyang Ping-Ping He Wei Xie Yu-Lin Tan Min Zhang Dan Liu Deng-Pei Tang Francisco S. Cayabyab Xi-Long Zheng Da-Wei Zhang Guo-Ping Tian Chao-Ke Tang 《Atherosclerosis》2014
Rationale
Macrophage accumulation of cholesterol leads to foam cell formation which is a major pathological event of atherosclerosis. Recent studies have shown that microRNA (miR)-19b might play an important role in cholesterol metabolism and atherosclerotic diseases. Here, we have identified miR-19b binding to the 3′UTR of ATP-binding cassette transporter A1 (ABCA1) transporters, and further determined the potential roles of this novel interaction in atherogenesis.Objective
To investigate the molecular mechanisms involved in a miR-19b promotion of macrophage cholesterol accumulation and the development of aortic atherosclerosis.Methods and results
We performed bioinformatics analysis using online websites, and found that miR-19b was highly conserved during evolution and directly bound to ABCA1 mRNA with very low binding free energy. Luciferase reporter assay confirmed that miR-19b bound to 3110-3116 sites within ABCA1 3′UTR. MiR-19b directly regulated the expression levels of endogenous ABCA1 in foam cells derived from human THP-1 macrophages and mouse peritoneal macrophages (MPMs) as determined by qRT-PCR and western blot. Cholesterol transport assays revealed that miR-19b dramatically suppressed apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux, resulting in the increased levels of total cholesterol (TC), free cholesterol (FC) and cholesterol ester (CE) as revealed by HPLC. The excretion of 3H-cholesterol originating from cholesterol-laden MPMs into feces was decreased in mice overexpressing miR-19b. Finally, we evaluated the proatherosclerotic role of miR-19b in apolipoprotein E deficient (apoE−/−) mice. Treatment with miR-19b precursor reduced plasma high-density lipoprotein (HDL) levels, but increased plasma low-density lipoprotein (LDL) levels. Consistently, miR-19b precursor treatment increased aortic plaque size and lipid content, but reduced collagen content and ABCA1 expression. In contrast, treatment with the inhibitory miR-19b antisense oligonucleotides (ASO) prevented or reversed these effects.Conclusion
MiR-19b promotes macrophage cholesterol accumulation, foam cell formation and aortic atherosclerotic development by targeting ABCA1. 相似文献11.
Aims
To investigate the effects of urokinase-type plasminogen activator (uPA) on proliferation and phenotypic transformation of rat mesangial cells (MCs) under high glucose conditions and its possible signal transduction pathway.Methods
Rat MC were divided into 4 groups: the control group, the high glucose group, the high glucose and wortmannin group, and the high glucose and uPA group. MC proliferation in all groups was detected by the 3-(4,5-dimethylthiazol-)-2,5-diphenyltetrazolium bromide (MTT) method. MC cell cycle was analyzed by flow cytometry. Expression of cyclin dependent kinase 2 (CDK2), and activity of the signaling protein Akt in MC were detected by Western blot. Expression pattern and quantity of α-smooth muscle actin (α-SMA) in MC were examined using laser confocal microscopy. The expression of plasminogen activator inhibitor-1 (PAI-1), and collagen IV in renal tissues in rats was tested with immunohistochemistry and Western blotting methods.Results
Activation of Akt induced by high glucose can be reduced significantly by wortmannin and uPA. There was no obvious change in CDK2 protein expression in different groups (P > 0.05). Expression of α-SMA in MC cytoplasm increased dramatically (P < 0.01). Expression of α-SMA decreased significantly in the high glucose and wortmannin group and the high glucose and uPA group compared with that of the high glucose group (P < 0.01). In diabetic rats, uPA down-regulated PAI-1 and collagen IV expression in mesangial matrix (P < 0.05).Conclusion
uPA antagonizes cell proliferation and phenotypic transformation of MCs induced by high glucose through inhibiting Akt signaling pathway. 相似文献12.
Rong Hui Du Si Yuan Qin Lu Sen Shi Zi Qian Zhou Xi Yu Zhu Juan Liu Ren Xiang Tan Wangsen Cao 《Atherosclerosis》2014
Objective
To develop alternative therapeutic strategy that reduces hypercholesterolemia, inflammation and atherosclerosis, we investigate if fumigaclavine C (FC), an indole alkaloid in structure, has anti-atherosclerosis function, and if so, what is the mechanism involved.Methods and results
We used ApoE-deficient (ApoE−/−) mice as an atherosclerosis model to examine if FC reduced aorta lesion size and improved serum lipid profiles. ApoE−/− mice at 6 weeks of age were fed on a western diet for 10 weeks before FC was administrated (5, 10 and 20 mg/kg) by gavage daily for additional 4 weeks. The mice were sacrificed at 20 weeks of age for examination. The atherosclerotic lesions were assessed with Oil Red O staining in the whole aorta and aortic sinus. Serum levels of triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and low density lipoprotein cholesterol (LDL-c) were determined enzymatically. Mouse macrophages were examined for lipid droplets inside cells. FC's effect on PPARγ and PPARγ signaling pathway were further investigated by western blot and luciferase assay. We found that FC decreased atherosclerotic lesion formation in ApoE−/− mice in a dose-dependent manner. Also FC improved lipid profiles in ApoE−/− mice and reduced the foam cell numbers of peritoneal macrophages. FC stimulated PPARγ signaling pathway proteins both in vitro and in vivo. FC enhanced PPARγ transactivation activity assayed by a PPRE reporter system.Conclusion
Our data indicated that FC activated PPARγ signaling pathway as well as its downstream proteins and had an effective role of anti-atherosclerosis. 相似文献13.
Hakamata H Miyazaki A Sakai M Sakamoto YI Horiuchi S 《Journal of atherosclerosis and thrombosis》1998,5(2):66-75
Macrophage or macrophage-derived foam cell death is one of the characteristic events in the development of cell-poor lipid-rich cores of the advanced atherosclerotic plaques. Although the in vivo mechanism for the death of macrophages is unclear, one possible candidate for the agent which induces macrophage cell death is oxidized low density lipoprotein (Ox-LDL). To investigate the mechanism of Ox-LDL-induced macrophage cell death, we have recently employed macrophage cell genetics and isolated mutant cells resistant to the cytotoxic effect of Ox-LDL from mutagenized populations of murine macrophage-derived J774 cells (Hakamata, H., Miyazaki, A., Sakai, M., Matsuda, H., Suzuki, H., Kodama, T., and Horiuchi, S. (1998) J. Lipid Res. 39, 482-494). The results obtained showed that one mutant form, JO21b cells, was characterized by reduced expression of type I and type II class A macrophage scavenger receptors (MSR-AI/AII) with a concomitant decrease in the uptake of Ox-LDL. Moreover, peritoneal macrophages obtained from MSR-AI/AII-knockout mice showed a higher resistance to the cytotoxic effect of Ox-LDL compared to those of their wild-type littermates. From these results, we have concluded that Ox-LDL cytotoxicity to macrophages is enhanced by effective endocytic uptake of Ox-LDL through MSR-AI/AII. These findings imply a possibility that formation of the cell-poor lipid-rich core is also enhanced by MSR-AI/AII-mediated uptake of Ox-LDL and subsequent macrophage cell death in atherosclerotic lesions. 相似文献
14.
Sandra N. Verhagen Marc P. Buijsrogge Aryan Vink Lex A. van Herwerden Yolanda van der Graaf Frank L.J. Visseren 《Atherosclerosis》2014
Objective
Perivascular adipose tissue (pvAT) may induce a local pro-inflammatory environment, possibly contributing to coronary atherosclerosis. We investigated whether there is a difference in adipocytokine production by pvAT near stenotic and non-stenotic coronary artery segments in patients with coronary artery disease (CAD).Methods
In patients undergoing CABG with or without valve replacement (n = 38) pvAT near stenotic and near non-stenotic coronary segments was harvested. PvAT was incubated ex vivo for 24 h. Concentrations of 23 adipocytokines were measured in the supernatants with a Multiplex assay. The number of macrophages (CD68, CD11c, CD206) and lymphocytes (CD45) in pvAT was determined. Differences between stenosis and control pvAT were tested with Wilcoxon signed rank test corrected for multiple comparisons.Results
Production of IL-5, IL-1α, IL-17, IL-18 and IL-23 was higher in control than stenosis pvAT samples (p < 0.0021). Macrophages were more abundant in stenosis than in control pvAT (median n/400× field: 2.3 IQR: 0.3–4.5 versus 1.2 IQR: 0.1–2.5). There was a predominance of M2 macrophages in both stenosis and control pvAT (median n/400× field: macrophages stenosis: M1: 0.0; M2: 1.0 p = 0.004; control: M1: 0.0; M2: 0.6 p = 0.013). The relation between adipocytokine production and macrophage infiltration was not different in stenosis and control pvAT.Conclusion
In patients with CAD, multiple adipocytokines were secreted at higher levels by pvAT near non-stenotic than near stenotic coronary artery segments. Furthermore, pvAT macrophages are associated with stenosis of the adjacent vessel. M2 macrophages were more abundant than M1 macrophages in pvAT. 相似文献15.
Sung Hyun Choi Seok Yun Jung Sae Mi Yoo Takayuki Asahara Wonhee Suh Sang-Mo Kwon Sang Hong Baek 《International journal of cardiology》2013
Background
Stem cells have a low expansion rate and are difficult to maintain in vitro. To overcome the problems of cardiovascular regeneration, we developed a novel method of stem cell cultivation in culture vessels with amine and carboxyl coatings.Methods and results
We isolated cardiac stem/progenitor cells from infant-derived heart tissue by using c-kit antibody (human cardiac-derived c-kit positive progenitor cells; hCPCc-kit +); the cells differentiated into endothelial cells, smooth muscle cells, and cardiomyocytes.To characterize the effect of surface modification on hCPCc-kit + expansion, cellular attachment, c-kit expression maintenance, and cardiomyocyte differentiation, we tested hCPCc-kit + cultured on non-coated (control), amine-coated (amine), and carboxyl-coated (carboxyl) vessels.Ex vivo proliferation, c-kit maintenance, and cellular attachment were significantly enhanced in the amine group. The amine coating also increased procollagen type I (pro-COL1) expression and increased phosphorylation signals, such as focal adhesion kinase (FAK) and cytosolic Src, as well as enhanced ERK/CDK2 signaling. In addition, there was significant downregulation of the stress signal transducer, JNK, in the amine group. However, cardiomyogenesis remained unchanged in the control, amine, and carboxyl groups.Conclusions
Although surface modifications had no effect on early induction cardiomyogenesis, amine-enriched surface modification may increase hCPCc-kit + expansion. The amine-enriched surface improved cellular proliferation and attachment during ex vivo hCPCc-kit + expansion, possibly by modulating intracellular signal transducers. 相似文献16.
Objective
Abdominal aortic aneurysms (AAA) are age-associated, life-threatening inflammatory dilations of the abdominal aorta. Human population studies have shown an association between obesity and AAA formation, but the molecular mechanisms underlying this connection remain largely unexplored. Adiponectin is an anti-inflammatory adipokine that is downregulated in obesity. In this study we evaluated the role of adiponectin in a model of AAA using apolipoprotein E/adiponectin double-knockout (Apoe−/−Apn−/−) mice.Approach and results
Angiotensin II (Ang II)-infusion in male Apoe−/−Apn−/− mice led to a higher incidence of AAA and a significant increase of maximal aortic diameter compared with that of Apoe−/− mice (2.12 ± 0.07 mm vs. 1.67 ± 0.09 mm, respectively at 28 days). Adiponectin deficiency augmented the early infiltration of macrophages and increased the expression of pro-inflammatory factors in the dilated aortic wall. MMP-2 and MMP-9 activation was also augmented in the aorta of Apoe−/−Apn−/− mice compared to Apoe−/− mice. These data suggest that the downregulation of adiponectin could directly contribute to the elevated incidence of AAA observed in obese individuals.Conclusions
Adiponectin attenuates Ang II-induced vascular inflammation and AAA formation in mice. 相似文献17.
Yutang Wang Smriti M. KrishnaJoseph Moxon Tam Nguyen DinhRoby J. Jose Hongyou YuJonathan Golledge 《Atherosclerosis》2014
Objective
To assess relevant features of abdominal aortic aneurysms (AAA) induced by calcium phosphate within a mouse model. Specifically we investigated: (1) whether apolipoprotein E deficiency and older age promoted AAA formation, and (2) whether the local application of calcium phosphate affected the size of distant aortic segments.Methods
AAA was induced by application of calcium phosphate to the infra-renal aortas of 3 and 7 month old male mice. AAA induction was assessed by calculating expansion of the infra-renal aortic diameter over 1–4 weeks. Aortic samples were assessed to quantify calcification, macrophages infiltration, elastic lamellar degradation and apoptosis. Blood pressure was measured by the tail cuff method, and plasma concentrations of total cholesterol, low density lipoprotein and very low density lipoprotein cholesterol, and pro-inflammatory cytokines were measured using commercially available kits. The maximum diameters of the aortic arch, thoracic and supra-renal aorta at sacrifice were measured by morphometry and the mean maximal diameter of these three aortic segments was calculated.Results
The median expansion of the infra-renal aorta 2 weeks after AAA induction was significantly greater in apolipoprotein E deficient (ApoE−/−) mice than in age- and gender-matched wild type controls [275.8% (IQR 193.8%–348.5%) versus 94.7% (IQR 47.8%–163.4%), P = 0.02]. The greater aortic expansion in ApoE−/− mice was associated with aortic calcification, macrophage infiltration, elastic lamellar degradation and apoptosis of cells in the media and adventitia. The plasma low density lipoprotein/very low density lipoprotein cholesterol concentrations 2 weeks after AAA induction were positively correlated with the expansion of the infra-renal aorta induced by calcium phosphate. The median expansion of the infra-renal aorta 2 weeks after AAA induction was similar in 3 and 7 month old wild type mice. The local administration of calcium phosphate was associated with an increase in the mean maximal diameter of distant aortic segments, but not associated with changes in the concentrations of pro-inflammatory markers in either the plasma or the spleen.Conclusion
This study suggests that apolipoprotein E deficiency, but not age, predisposes to AAA induced within the calcium phosphate model. Increased AAA expansion in ApoE−/− mice was associated with calcification, macrophage infiltration, elastic lamellar degradation, and cell apoptosis. Local application of calcium phosphate also promoted dilation of distant aortic segments. 相似文献18.
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Xintong Wang Angela L. Zachman Young Wook Chun Fang-Wen Shen Yu-Shik Hwang Hak-Joon Sung 《International journal of cardiology》2014