DigitalUM :: Browsing by Subject "Atherosclerosis"

Browsing by Subject "Atherosclerosis"

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Open Access
C-reactive protein levels are associated with the progression of atherosclerotic lesions in rabbits
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Yu, Qi; Li, Yafeng; Wang, Yanli; Zhao, Sihai; Yang, Peigang; Chen, Yulong; Fan, Jianglin; Liu, Enqi
Elevated plasma levels of C-reactive protein (CRP) are associated with increased risk of cardiovascular disease. CRP immunoreactive protein is also detected in the lesions of atherosclerosis. However, it is not known whether the CRP contents of atherosclerotic lesions are associated with the initiation and progression of atherosclerosis. To examine this hypothesis, we investigated different types of atherosclerotic lesions of rabbits fed with a cholesterol-rich diet for 6, 12, 16, and 28 weeks and examined their relationship with CRP. We measured the aortic atherosclerotic area, macrophages, and smooth muscle cells along with CRP contents in the lesions. Atherosclerotic lesions of aortas began to form at 6 weeks and were characterized by accumulation of macrophages in the intima, and lesions became more fibrotic in the advanced stage. Both plasma CRP levels and the lesional CRP contents were associated with the lesion size. Our results suggest that plasma CRP, as well as lesional CRP, associated with the formation and progression of atherosclerotic lesions.
Open Access
Caracterización del pollo como biomodelo experimental en arteriosclerosis: lesiones en troncos supra-aórticos
(Murcia: Servicio de Publicaciones de la Universidad de Murcia, 2011) Sánchez Polo, María Teresa; García Pérez, Bartolomé; Adánez Martínez, María de Gracia; Martin, A.; Ayala de la Peña, Ignacio; Castells Mora, María Teresa; Biología Celular; Medicina y Cirugía Animal
La enfermedad cardiovascular es hoy en día la primera causa de mortalidad en las sociedades desarrolladas. Dada la complejidad del desarrollo de la lesión aterosclerótica en el ser humano resulta interesante investigar en modelos animales en los que dicho proceso sea semejante a la enfermedad humana. El pollo, al igual que otras aves, es capaz de desarrollar arteriosclerosis aórtica y coronaria de forma natural o espontánea, e inducida por una dieta enriquecida en colesterol. Teniendo en cuenta que la mayoría de los trabajos publicados describen las lesiones en segmentos aórticos y la variedad de métodos de inducción de la arteriosclerosis, el objetivo de esta investigación es caracterizar de manera adecuada en el modelo aviar utilizado, las lesiones arterioscleróticas de troncos supra-aórticos en un grupo experimental con respecto a un grupo control. Se emplearon 20 pollos de la raza White Leghorn divididos en dos grupos (control y aterogénico) que recibían una dieta normal o hiperlipémica respectivamente durante un periodo de 6 meses. Se sacrificaron entonces los animales para llevar a cabo el estudio bioquímico del plasma (perfil lipídico), evaluación histológica de los troncos supra-aórticos y valoración semicuantitativa de las lesiones según la clasificación de Stary. Se observaron diferencias estadísticamente significativas entre ambos grupos para los diferentes parámetros bioquímicos estudiados y para la cuantificación del grado de lesión de Stary. En el grupo aterogénico se observó un endotelio conservado, con íntimas muy aumentadas de tamaño (10 veces el tamaño del grupo control) y muy desorganizadas. En conclusión, estos hallazgos confirman el uso del pollo como biomodelo experimental para el estudio de la arteriosclerosis en troncos supra-aórticos, y podrían ser empleados como referencia para futuros estudios intervencionistas.
Open Access
CD9 expression in vascular aging and atherosclerosis
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Kim, Jae-Ryong; Cho, Joon Hyuk
CD9 is a transmembrane glycoprotein belonging to the tetraspanin family. CD9 expression has been reported to be associated with cellular signaling, cell adhesion, cell migration, and tumor related processes. The aim of this study was to examine the immunohistochemical expression of CD9 in vascular senescence and atherosclerosis. One hundred and twenty samples of normal young arteries (obtained from individuals aged 0-60 years), 40 samples of normal old arteries (obtained from individuals aged 61-80 years), and 67 samples of atherosclerotic arteries were obtained from surgically resected specimens. Tissue microarray blocks were prepared for immunohistochemical staining. Immunohistochemical staining detected CD9 expression in 10.8% (13 of 120 samples) of normal young arteries and 30.0% (12 of 40 samples) of normal old arteries. CD9 expression was absent or mildly present in the smooth muscle cells and endothelial cells of normal arteries. Normal old arteries showed significantly higher expression of CD9 than normal young arteries (P<0.01). Atherosclerotic arteries showed moderate or strong CD9 expression (65 of 67 samples, 97.0%), which was observed in the smooth muscle cells, endothelial cells, macrophages, and atheromatous plaques. CD9 was significantly expressed in the atherosclerotic arteries compared to normal young and old arteries (P<0.01). The results suggest that CD9 expression may play an important role in the vascular senescence and pathogenesis of atherosclerosis.
Open Access
Critical and diverse in vivo roles of apoptosis signal-regulating kinase 1 in animal models of atherosclerosis and cholestatic liver injury
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Yamada, Sohsuke; Noguchi, Hirotsugu; Tanimoto, Akihide
. Apoptosis plays pivotal in vivo roles in not only vital processes, such as cell turnover and embryonic development, but also various inflammatory disorders. However, the role of apoptosis by vascular and hepatic cells in the respective progression of atherosclerosis and liver injury remains controversial. Apoptosis signalregulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase family member that is activated through distinct mechanisms in response to various cytotoxic stressors. ASK1, ubiquitously expressed, is situated in an important upstream position for many signal transduction pathways, which subsequently induce inflammation and/or apoptosis. Our serial in vivo studies have uniquely reported that the expression of phosphorylated ASK1 is variably seen in atherosclerotic lesions or bile-duct-ligation (BDL)- induced injury livers. In mice genetically deficient of ASK1 (ASK1-/- ), activated ASK1 signaling accelerates high-cholesterol-diet-induced necrotic lipid core formation by inducing macrophage apoptosis and enhances ligation injury-induced vascular remodeling via pro-inflammatory reactions and by stimulating apoptosis of smooth muscle cells. In contrast, in models of BDL-induced cholestatic liver injury, the pathogenic roles of ASK1-mediated early necro-inflammation, but not apoptosis, and the proliferation of hepatocytes and cholangiocytes are crucial in subsequent peribiliary fibrosis/fibrogenesis. These animal models of acute to chronic inflammatory diseases show that stimulated ASK1 signaling critically and diversely regulates not only hypercholesterolemia-induced atherosclerosis and injury-induced arteriosclerosis, but also the acute and subacute-to-chronic phase of BDL-induced cholestasis. We herein review the diverse, key in vivo roles of ASK1 signaling in the pathogenesis of inflammatory disorders closely related to metabolic syndrome.
Open Access
Demonstration of an add-on effect of probucol and cilostazol on the statin-induced anti-atherogenic effects
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2014) Wang, Yanli; Bai, Liang; Lin, Yan; Guan, Hua; Zhu, Ninghong; Chen, Yulong; Li, Yafeng; Gao, Shoucui; Zhao, Sihai; Fan, Jianglin; Liu, Enqi
Statins are often prescribed for treatment of cardiovascular diseases, although there are still many patients who cannot be effectively treated by statins alone. Both probucol and cilostazol exhibit antiatherogenic effects. In the current study, we attempted to investigate whether a probucol and cilostazol combination had any add-on effects on atorvastatin. To examine this hypothesis, we fed Japanese white rabbits with a cholesterol-rich diet supplemented with atorvastatin alone (Statin group), probucol and cilostazol (PC group), atorvastatin, probucol and cilostazol (APC group), and compared their effects on plasma lipids and aortic atherosclerosis. All three drug-treated groups had lowered total cholesterol levels compared with the vehicle group but high-density lipoproteins cholesterol levels of the atorvastatin group were higher than other groups. Although aortic atherosclerosis was significantly reduced in all drug-treated groups, the most prominent atheroprotective effect was seen in APC group (APC: 67% reduction> PC: 43% reduction> Statin group: 42% reduction over the vehicle). Morphometric analysis revealed that the reduced aortic atherosclerosis in all three groups was mainly attributed to the reduction of intimal macrophages and smooth muscle cells. These results suggest that a combination of probucol and cilostazol with statin enhances statin’s anti-atherogenic functions, which may be beneficial for those patients who are less responsive to statin therapy alone.
Open Access
Effect of diet/atorvastatin on atherosclerotic lesions associated to nonalcoholic fatty liver disease in chickens
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2015) Sánchez-Polo, Maria T.; García Pérez, Bartolomé; Martín, Antonia; Adánez Martínez, María de Gracia; Ayala de la Peña, Ignacio; Castells Mora, María Teresa
Comparative histological examination of both liver and the supra-aortic arteries have not previously examined the consequences of atherosclerosis and nonalcoholic fatty liver disease (NAFLD), and their response to diet and atorvastatin therapy. This study evaluates the effects of diet alone or in combination with atorvastatin therapy on the progression/regression of atherosclerosis and its correlation with NAFLD. This research was performed on a cohort of chickens on standard (SD) or hyperlipidemic diets (HD), either with or without atorvastatin therapy. The development of atherosclerotic lesions was assessed by histology, immunohistochemistry and quantitative image analysis and correlated with liver histology. The lowest levels of atherosclerotic lesions were found in animals on the HD for 3 months, followed by 3 months of SD in combination with oral atorvastatin. There was a strong association between the histologic findings of atherosclerosis and those of NAFLD. These studies show that standard diet and atorvastatin therapy can positively affect both arterial and hepatic lesions, influencing the regression of the changes. These results support the hypothesis that NAFLD and atherosclerosis may be actually two aspects of a shared disease and suggest the possibility of regression of both disorders with dietary and pharmacologic manipulations.
Open Access
Embryonic stem cells markers are present within rabbit atherosclerotic plaques
(Murcia : F. Hernández, 2008) Zulli, Anthony; Buxton, Brian F.; Black, M. Jane; Hare, David L.
Recent evidence suggests that smooth muscle cells within atherosclerotic plaques originate from vascular progenitor cells. We have previously shown that smooth muscle cells and macrophages present within rabbit atherosclerotic plaques are positive for factors of the renin angiotensin and nitric oxide systems as well as the hematopoietic stem-cell marker CD34 and the panleukocyte marker CD45. To explore the idea that these cells are of primitive types, immunohistochemistry was used to identify pluripotent embryonic stem cells (ESC) markers (Oct-4, SSEA1,3,4, TRA1-60, 81) in these plaques and to compare these to intimal thickening. Objective: To immunolocalise ESC markers in rabbit aortic intimal thickening and atherosclerotic plaques. Design: New Zealand White rabbits were fed either a control (Con) diet, 0.5% cholesterol (Chol) or 1% methionine (Meth) for 12 weeks. Animals were perfusion fixed, aortae excised and processed for paraffin. Immunohistochemistry was performed by standard techniques. Results: Oct-4, SSEA 1, 3 and 4, TRA-1-60 and TRA-1-81 were all present within in atherosclerotic plaques. However, some cells were not positive for TRA-1-60 and TRA-1-81. In fact, positive TRA-1-81 macrophages were uncommon, and positive TRA-1-81 smooth muscle cells were rare. Intimal thickening in Meth did not show any TRA-1-81 positive cells Conclusions: Macrophages and smooth muscle cells within atherosclerotic plaques express markers of ESC. These results suggest that cells within these plaques are primitive and might differentiate into other types of cells.
Open Access
Enhanced accumulation of the isoprostane, 8-epi-PGF2a, in human aortic and pulmonary valves of patients with coronary heart disease
(Murcia : F. Hernández, 2002) Mehrabi, M.R.; Serbecic, N.; Ekmekcioglu, C.; Tamaddon, F.; Wild, T.; Plesch, K.; Sinzinger, H.; Glogar, H.D.
The aim of the present study was to investigate whether the isoprostane 8-epi-PGF2a differently accumulates in semilunar valves of patients suffering from coronary heart disease (CHD, n=19) as compared to valves from healthy heart donors (controls, n=6). Sections from isolated aortic and pulmonary valves were analyzed by semiquantitative immunohistochemistry. The 8-epi-PGF2a-content was determined by using a specific radioimmunoassay. The accumulation of 8-epi-PGF2a in both valves was higher in CHD-patients in comparison to controls (Aortic valves: 36.49±11.26 % vs. 15.78±3.04 %; pulmonary valves: 46.79±9.80 % vs. 14.99±3.57 %). The results from the radioimmunoassay revealed comparable findings in both groups (CHD vs. controls: 395.95±86.09 vs. 139.50±47.46 pg/mg protein in the aortic valves and 430.47±76.30 vs. 147.33±53.84 pg/mg protein in pulmonary valves). Pulmonary valves seem to be more susceptible to oxidative stress than aortic valves as evidenced by a higher accumulation of 8-epi-PGF2a in CHD patients. Considering the data presented in this study, we suggest that 8-epi-PGF2a is a valuable indicator of oxidative injury in human semilunar valve
Open Access
Evidence that dendritic cells infiltrate atherosclerotic lesions in apolipoprotein E-deficient mice
(Murcia : F. Hernández, 2001) Bobryshev, Y.V.; Taksir, T.; Freeman, M.W.
Earlier we reported that atherosclerotic lesions of apoE-deficient mice contained cells which stained positively with anti-S-100 antibody and that cells exhibiting the ultrastructural features of dendritic cells were present in the aortic lesions. These observations suggested that dendritic cells might be involved in mouse atherosclerosis. By employing DEC-205 and MIDC-8 antibodies specific for dendritic cells, the present study has established that dendritic cells indeed accumulate in atherosclerotic lesions of apoE-deficient mice. Finding dendritic cells infiltrating atherosclerotic lesions in apoE-deficient mice offers the possibility of investigating the migratory routes of dendritic cells and their involvement in T-cell activation.
Open Access
Expression of CCL2 signaling pathway genes in patients with periodontitis and atherosclerosis
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Zhao, Yuxia; Wang, Lianqun; Dong, Rui; Cheng, Xuejun; Jia, Liqun; Qu, Dan; Zhang, Lin
Objective. Periodontitis and atherosclerosis are chronic inflammatory diseases characterized by leukocyte infiltration. We investigated the expression of CCL4, CCR5, c-Jun, c-Fos, NF-κB, and CCL2 as well as the possible mechanism involved in the regulation of CCL2 in human periodontitis tissues and atherosclerotic aorta based on previous research on the CCL4/CCR5/c-Jun and c-Fos/CCL2 pathway leading to CCL2 expression in collagen-induced arthritis (CIA) rat. Methods. Sixty-five volunteers were recruited and the condition of their gingiva and coronary arteries were assessed. The subjects were divided into four groups: healthy control, chronic periodontitis (CP), coronary artery diseases (CAD), and noncoronary artery diseases (non-CAD). Total RNA was isolated from gingiva in periodontitis patients and control populations and from the aorta in patients with and without CAD. PCR was used to examine CCL4, CCR5, c-Jun, c-Fos, NF-κB, and CCL2 levels. The production of CCL2 in the gingiva and aorta was analyzed by immunostaining. Results. PCR revealed that CCL4, CCR5, and CCL2 mRNA levels were increased in CP patients' gingivae and aortas from coronary artery bypass grafting (CABG) patients. Marked c-Jun, c-Fos, and NF-κB gene productions were detected in CP patients’ gingivae but did not show statistical differences between the CAD and non-CAD groups. Stronger immunoreactivity against CCL2 was observed in periodontitis gingiva and aorta from CABG patients. Conclusions. Our findings suggest that the CCL4/CCR5/c-Jun and c-Fos/CCL2 pathways may be involved in CCL2 expression in periodontitis. CCL4, CCR5, and CCL2 might act as possible nodes to link the presence of periodontitis and atherosclerosis.
Open Access
Extracellular matrix components in atherosclerotic arteries of Apo E/LDL receptor deficient mice: An immunohistochemical study
(Murcia : F. Hernández, 2004) Ström, Å.; Ahlqvist, E.; Franzé, Adela; Heinegård, D.; Hultghrdh-Nilsson, A.
During accelerated vascular remodeling such as in atherosclerosis, the composition of the extracellular matrix becomes altered. The matrix components of the diseased artery influence cellular processes such as adhesion, migration and proliferation. Furthermore, in atherosclerosis, the inability of the cells within the lesion to produce a mechanically stable matrix may lead to plaque rupture. In this immunohistochemical study of atherosclerotic mice aorta, we have reviewed the presence of ECM components with roles in maintaining tissue structure and function. These components include osteopontin and COMP as well as the leucine rich repeats proteins decorin, PRELP, and fibromodulin. Immunohistochemistry demonstrated presence of osteopontin, COMP, decorin, PRELP and fibromodulin in lesion areas of ApoE/LDLr deficient mice. Some advanced lesions exhibited areas of cartilage-like morphology and were shown to represent cartilage by their content of the cartilage specific proteins collagen II and aggrecan. The results suggest that cartilageassociated cell/collagen binding ECM proteins may be involved in the pathogenesis of atherosclerosis.
Open Access
Frontotemporal dementia-associated protein "phosphorylated TDP-43" localizes to atherosclerotic lesions of human carotid and main cerebral arteries
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Umahara, Takahiko; Uchihara, Toshiki; Hirao, Kentaro; Shimizu, Soichiro; Hashimoto, Takao; Akimoto, Jiro; Kohno, Michihiro; Hanyu, Haruo
The transactivation response DNA binding protein (TARDP) of 43 kDa (TDP-43) is a nuclear protein pivotal in RNA processing. Because phosphorylated (p) TDP-43 has been identified as a component of ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), it is considered to play a major role in neurodegenerative processes. We investigated the immunolocalization of pTDP-43 in atherosclerotic lesions of human carotid and main cerebral arteries. Furthermore, we investigated the co- localization between pTDP-43 and 14-3-3 eta isoform or high mobility group box 1 (HMGB1). pTDP-43 localized in the cytoplasm of many foamy macrophages located in the periphery of lipid-rich necrotic cores, and in the cytoplasm of infiltrated smooth muscle cell-like cells. pTDP-43 co-localized the 14-3-3 eta isoform in carotid plaques. pTDP-43 also co- localized HMGB1. This is the first demonstration of pTDP-43 immunolocalization in human carotid and main cerebral artery plaques. We believe that demonstration of the localization of pTDP-43 in atherosclerotic lesions is important as this may contribute to the establishment of the clinical diagnostic imaging of FTLD and ALS using the pTDP-43 epitope. Moreover, this finding may be useful for further understanding the role of TDP in cell death.
Open Access
Heme oxygenase-1 and cardiovascular disease
(Murcia : F. Hernández, 2006) Immenschuh, S.; Schröder, H.
Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-controlling enzyme of heme degradation. HO-1 is up-regulated by a host of oxidative stress stimuli and has potent cytoprotective and antiinflammatory functions via decreasing tissue levels of the prooxidant heme along with production of bilirubin and the signaling gas carbon monoxide. This review deals with recent findings that highlight the emerging significance of HO-1 in cardiovascular disease. Evidence is presented on how heme and various oxidative stress stimuli may cause endothelial cell dysfunction and how HO-1 may counteract the detrimental effects of oxidative stress in the endothelium. Recent advances in the understanding of the role of endothelial HO-1 for the regulation of the inflammatory response are summarized, including the modulation of leukocyte recruitment and transmigration through the endothelial barrier. Furthermore, experimental evidence from various cell culture and animal models is discussed which suggests an association of HO-1 with the complex sequence of events that cause atherosclerosis. In the second part of the review we present potential strategies that apply HO- 1 as a therapeutic target in the treatment of cardiovascular disease. Specific inducers of HO-activity which may ultimately lead to the development of clinically relevant pharmacological applications are introduced.
Open Access
Identification of dendritic cells in aortic atherosclerotic lesions in rats with diet-induced hypercholesterolaemia
(Murcia : F. Hernández, 2002) Ozmen, J.; Bobryshev, Y.V.; Lord, R.S.A.; Ashwell, K.W.S.
We have previously identified dendritic cells (DCs) in the intima of human large arteries. These vascular DCs are common in atherosclerotic lesions but their immature forms are also present in normal arterial intima. Pathophysiological studies on vascular DCs are limited because they have only been studied in human specimens obtained at operation or post-mortem. The aim of the current study was to determine whether DCs participate in the development of atherosclerotic lesions in hypercholesterolemic rats. Male Wistar rats were divided into a control (n=13) and experimental cohort (n=48). The experimental animals were fed an atherogenic diet and 1% saline, while the controls were fed standard rat cubes and water. The aortas were obtained from both groups at 10, 20, and 30 weeks following commencement of the diet. An en face immunohistochemical technique, routine section i m m u n o h i s t o c h e m i s t r y, and transmission electron microscopy were used to detect the presence of DCs in the aortas. Examination of the aortas showed that S100+ cells with dendritic cell morphology were present in the aortic intima of hypercholesterolemic rats. The S100+ DCs displayed immunopositivity for OX-62 and MHC Class II antibodies. Within various types of atherosclerotic lesions, these cells were clustered throughout the intima but were especially prominent around arterial branch-points where they co-localized with various cell types, including T-cells and macrophages. Ultrastructural analysis confirmed the presence of cells with characteristics typical of DCs. These features included the presence of a welldeveloped tubulovesicular system, dendritic processes, and a lack of secondary lysosomes and phagosomes. This study establishes the presence of DCs in the aortic intima of rats with diet-induced atherosclerosis. The presence of DCs in this model of experimental atherogenesis could provide a new approach to investigating the function of DCs and may help clarify the immune-inflammatory mechanisms underlying atherosclerosis.
Open Access
In-situ analysis of mast cells and dendritic cells in coronary atherosclerosis in chronic kidney disease (CKD)
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Wachter, D.L.; Neureiter, Daniel; Câmpean, V.; Hilgers, K.F.; Büttner Herold, M.; Daniel, C.; Benz, K.; Amann, K.
Aims. Mast cells (MC) and dendritic cells (DC) have immune modulatory function and can influence T-cell activity. Both cell types have been found in atherosclerotic plaques and are thought to play an important role for plaque stability. Compared to matched segments of the non-renal population, patients with chronic kidney disease (CKD) show a more pronounced and more aggressive course of atherosclerosis with higher plaque calcification and significantly higher complication rates. It was the aim of this study to analyze the number and localization of MCs and DCs, macrophages, T- and B-cells as well as the expression of markers of inflammation such as CRP and NFκΒ in calcified and non-calcified atherosclerotic plaques of patients with CKD and control patients. Methods. Fifty coronary atherosclerotic plaques from patients with endstage CKD (CKD, n=25) and control (n=25) patients were categorized according to the Stary classification and investigated using immunohistochemistry (markers for MC, DC, T, B, macrophage and NFκΒ). Expression was analyzed separately for the complete plaque area as well as for the different plaque subregions and correlations were analyzed. Results. We found only very few DCs and MCs per lesion area with slightly increased numbers in calcified plaques. MCs per plaque area were significantly more frequent in CKD than in control patients and this was independent of plaque calcification. MCs were most frequently found in the shoulder and basis of the plaque. DCs per plaque area were significantly less in calcified plaques of CKD compared to control patients. In control, but not in CKD patients, DCs were significantly more frequent in calcified than in non-calcified plaques. Within the plaques, DCs were similarly distributed between all 4 subregions. Conclusions. Coronary atherosclerotic plaques of CKD patients showed a significantly higher number of MCs whereas DCs were less frequent compared to control patients particularly if plaques were calcified. These findings might indicate a potential proinflammatory role of MCs, but not of DCs in atherosclerotic lesions of CKD patients, adding another characteristic of advanced atherosclerosis in these patients.
Open Access
Intracellular cholesterol trafficking
(Murcia : F. Hernández, 1999) Sviridov, D.
The overall picture of intracellular cholesterol trafficking is very complex. The transfer of cholesterol within the cell depends on the contribution of several trafficking mechanisms. The known elements of cholesterol trafficking machinery include clathrin-coated pits, scavenger receptor type B1, caveolae, phospholipd rafts, Niemann-Pick C disease protein, sterol carrier protein 2, multidrug resistance protein, microsomal triglyceride transfer protein and steroidogenic acute regulation protein. Several pathways of intracellular cholesterol trafficking, for example retroendocytosis and cholesterol absorption in the intestine, are yet to be connected to specific structural elements. The contribution of different pathways depends on cell type, the source and destination of cholesterol and cellular cholesterol content and requirements. Some pathways are found in most, if not all, cell types, while others are associated with the specialized function of a particular cell type, for example, lipoprotein assembly in the liver or intestine and steroid hormone synthesis in steroidogenic tissue. Certain routes of intracellular cholesterol trafficking are heavily backed up by several auxiliary pathways, others entirely depend on a single functional element. In this review we describe the intracellular machinery involved in the intracellular transfer of cholesterol and give an overview of both the general and specialized pathways of intracellular cholesterol trafficking known to date.
Open Access
Laminin isoforms in atherosclerotic arteries from mice and man
(F. Hernández y J.F. Madrid. Murcia: Universidad de Murcia, Departamento de Biología Celular e Histología., 2011) Rauch, Uwe; Saxena, Amit; Lorkowski, Stefan; Rauterberg, Jürgen; Björkbacka, Harry; Durbeej, Madeleine; Hultgårdh-Nilsson, Anna
The properties of the arterial vasculature depend to a large extent on the activities of smooth muscle cells, which, in turn, are determined by their extracellular environment. During pathological conditions, such as atherosclerosis, this interaction is altered. In close proximity to medial smooth muscle cells are basement membrane components, such as different isoforms of laminin. These proteins can have great impact on cellular function via interaction with cell surface integrins. However, knowledge of laminins in smooth muscle cell basement membranes during normal and pathological conditions is scarce. Therefore, we have analyzed the presence of laminin isoforms in atherosclerotic lesions of apolipoprotein E (ApoE)-deficient mice. Our study revealed that the laminin chain isotype composition within atherosclerotic plaque tissue was different from the chain composition in the media. In addition, obvious differences in laminin chain composition could be observed in areas of the media, which were or were not associated with plaque tissue. Our major findings demonstrate that laminin gamma3 was exclusively present in media associated with plaque tissue. Laminin alpha2 was also enriched in these medial areas. Plaque tissue was predominantly enriched in laminin alpha5 chains. This general distribution applied to lesions both with and without a fibrous cap-like structure. The differential distribution of laminin chains were partially accompanied by changes in the presence of the integrin alpha subunits 7 and V. The distribution of laminin chains in human atherosclerotic arteries, with different size and morphology, grossly resembled their distribution in mouse arteries.
Open Access
Lipid droplet associated proteins:an emerging role in atherogenesis
(Murcia: F. Hernández, 2011) Buers, Insa; Hofnagel, Oliver; Ruebel, Anneke; Severs, Nicholas J.; Robenek, Horst
Coronary heart disease and stroke, caused by rupture of atherosclerotic plaques in the arterial wall, are the major causes of death in industrialized countries. A key event in the pathogenesis of atherosclerosis is the transformation of smooth muscle cells and in particular of macrophages into foam cells, a result of massive accumulation of lipid droplets. It is well known that the formation of these lipid droplets is a result of the uninhibited uptake of modified lipoproteins by scavenger receptors. However, only more recently has it become apparent that a special set of lipid droplet associated proteins - the PAT protein family (perilipin, adipophilin, TIP47, S3-12 and OXPAT) - is fundamental to the formation, growth, stabilization and functions of lipid droplets. Here we review recent findings and assess the current state of knowledge on lipid droplets and their PAT proteins in atherogenesis.
Open Access
Low density lipoproteins and mitogenic signal transduction processes: Role in the pathogenesis of renal disease
(Murcia : F. Hernández, 2002) Kamanna, V.S.
Abnormalities in lipid and lipoprotein metabolism are commonly observed in patients with chronic renal disease. Specifi c a l l y, hyperlipidemia and the glomerular deposition of atherogenic lipoproteins (e.g., Low density lipoprotein, LDL; and its oxidized variants) are implicated in key pathobiological processes i nvo l ved in the development of glomerular disease, including stimulation of monocyte infiltration into the mesangial space, mesangial cell hy p e r c e l l u l a r i t y, and mesangial extracellular matrix deposition. This rev i ew discusses recent understanding of glomerular mitogenic responses, intracellular signaling events associated with mesangial hypercellularity in renal diseases, and the participation of cholesterol and atherogenic lipoproteins in intracellular signaling pathways involved in mesangial cell proliferation. G e n e r a l l y, the mitogenic intracellular signaling p a t h ways are regulated by the activation of series of transmembrane and cytoplasmic protein tyrosine kinases that converge into the activation of Ras and down-stream m i t o g e n - a c t ivated protein kinase (MAP kinase). A c t ivated MAP kinase, through translocating into the nucleus and the activation of various transcription factors and protooncogenes, regulate cell proliferation. The importance of mitogenic intracellular signaling in mesangial proliferative disease has only recently been recognized and showed that the activation of MAP kinase and/or cy c l i n / cyclin-dependent kinases play crucial role in different phases of cell growth cycle and hypercellularity of glomerular cells in va r i o u s experimental renal diseases. Using glomerular mesangial cells as an in-vitro model system, studies from our laboratory indicated that the accumulation of LDL and more potently its oxidized forms within the glomerulus, through the activation of membrane receptor tyrosine kinases (e.g., EGF receptor), activate Ras and MAP kinase signaling cascade leading to DNA synthesis and subsequent mesangial cell proliferation. These data suggest that atherogenic lipoproteins may act as one of the major endogenous modulators for mitogenic signaling response and cell proliferation within the glomerulus. It is reasonable to speculate that the correction or reduction of hy p e r l i p i d e m i a , glomerular lipid deposition, and the pro-oxidative milieu within the glomerulus, through the inhibition of mitogenic signaling events, may provide protective e nvironment against mesangial hypercellularity and subsequent matrix deposition, and the progression of renal disease.
Open Access
Medial and adventitial macrophages are associated with expansive atherosclerotic remodeling in rabbit femoral artery
(Murcia : F. Hernández, 2008) Yamashita, A.; Shoji, K.; Tsuruda, T.; Furukoji, E.; Takahashi, M.; Nishihira, K.; Tamura, S.; Asada, Yujiro
Expansive vascular remodeling is considered a feature of vulnerable plaques. Although inflammation is upregulated in the media and adventitia of atherosclerotic lesions, its contribution to expansive remodeling is unclear. We investigated this issue in injured femoral arteries of normo- and hyperlipidemic rabbits fed with a conventional (CD group; n=20) or a 0.5% cholesterol (ChD group; n=20) diet. Four weeks after balloon injury of the femoral arteries, we examined vascular wall alterations, localization of macrophages and matrix metalloproteases (MMP)-1, -2, -9, and extracellular matrix. Neointimal formation with luminal stenosis was evident in both groups, while expansive remodeling was observed only in the ChD group. Areas immunopositive for macrophages, MMP-1, -2 and -9 were larger not only in the neointima, but also in the media and/or adventitia in the injured arterial walls of the ChD, than in the CD group. Areas containing smooth muscle cells (SMCs), elastin and collagen were smaller in the injured arterial walls of the ChD group. MMP-1, -2 and -9 were mainly localized in infiltrating macrophages. MMP-2 was also found in SMCs and adventitial fibroblasts. Vasa vasorum density was significantly increased in injured arteries of ChD group than in those of CD group. These results suggest that macrophages in the media and adventitia play an important role in expansive atherosclerotic remodeling via extracellular matrix degradation and SMC reduction.