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Human Lipoxygenase Pathway Gene Variation and Association with Markers of Subclinical Atherosclerosis in the Diabetes Heart Study  [PDF]
Kathryn P. Burdon,Megan E. Rudock,Allison B. Lehtinen,Carl D. Langefeld,Donald W. Bowden,Thomas C. Register,Yongmei Liu,Barry I. Freedman,J. Jeffrey Carr,Catherine C. Hedrick,Stephen S. Rich
Mediators of Inflammation , 2010, DOI: 10.1155/2010/170153
Abstract: Aims. Genes of the 5-lipoxygenase pathway are compelling candidates for atherosclerosis. We hypothesize that polymorphisms in ALOX12, ALOX15, ALOX5, and ALOX5AP genes are associated with subclinical atherosclerosis in multiple vascular beds. Methods. Families with two or more siblings with type 2 diabetes and their nondiabetic siblings were studied as part of the Diabetes Heart Study (DHS). European American diabetic ( ) and nondiabetic ( ) siblings were genotyped for SNPs in the ALOX12, ALOX15, ALOX5, and ALOX5AP genes. Subclinical measures of atherosclerosis (IMT, coronary (CorCP), carotid (CarCP) and aortic (AorCP) calcified plaque) were obtained. Results. Associations were observed between ALOX12 with CorCP, ALOX5 with CorCP, AorCP, and IMT, and ALOX5AP with CorCP and CarCP, independent of known epidemiologic risk factors. Further, lipoxygenase pathway SNPs that were associated with measures of atherosclerosis were associated with markers of inflammation (CRP, ICAM-1) and calcification (MGP). Conclusions. Polymorphisms within ALOX12, ALOX5, and ALOX5AP are genetically associated with subclinical atherosclerosis and with biomarkers of disease in families with type 2 diabetes. These results suggest that variants in lipoxygenase pathway genes may have pleiotropic effects on multiple components that determine risk of cardiovascular disease. 1. Introduction Atherosclerosis is thought to be the result of chronic inflammation of the artery wall although the pathways and factors that initiate and modulate the inflammatory response in atherosclerosis have yet to be completely resolved [1]. Metabolites of arachidonic acid are strong candidates that are recognized for their inflammatory properties. The mouse 5-LO gene, ALOX5, has been shown to contribute to the development of atherosclerosis [2]. Variants in the human homologue (ALOX5) are associated with carotid artery intima-media thickness (IMT) [3]. FLAP (5-lipoxygenase activating protein), encoded by the ALOX5AP gene, likely acts as an arachidonic acid-binding and transfer protein to facilitate 5LO activity [4]. Single SNPs and haplotypes of ALOX5AP have been associated with myocardial infarction in multiple populations [5–7]. Human 12-lipoxygenase (encoded by ALOX12) and 15-lipoxygenase (encoded by ALOX15) have been localized to atherosclerotic plaques, suggesting that 12/15LO activity is involved in the development of atherosclerosis [8–10]. Overexpression of human 15-LO in mouse vascular endothelial cells increased markers of atherosclerosis [11]. Human aortic endothelial cells cultured in chronically
Misrepair mechanism in the development of atherosclerotic plaques  [PDF]
Jicun Wang-Michelitsch,Thomas M. Michelitsch
Quantitative Biology , 2015,
Abstract: Atherosclerosis is a disease characterized by the development of atherosclerotic plaques in arterial endothelium. The atherosclerotic plaques in a part of arterial wall are inhomogeneous on size and on distribution. In order to understand this in-homogeneity, the pathology of atherosclerotic plaques is analyzed by Misrepair mechanism, a mechanism proposed in our Misrepair-accumulation aging theory. I. Development of an atherosclerotic plaque is a result of repair of injured endothelium. Because of infusion and deposition of lipids beneath endothelial cells, the repair has to be achieved by altered remodeling of local endothelium. Such a repair is a manifestation of Misrepair. During repair, smooth muscular cells (SMCs) are clustered and collagen fibers are produced to the lesion of endothelium for reconstructing an anchoring structure for endothelial cells and for forming a barrier to isolate the lipids. II. Altered remodeling (Misrepair) makes a local part of endothelium have increased damage sensitivity and reduced repair-efficiency; thus this part of endothelium will have increased risk for injuries, for lipid-infusion and for Misrepairs. Focal accumulation of Misrepairs and focal deposition of lipids result in development of a plaque. III. By a viscous circle between lipid-infusion and endothelium-Misrepair, growing of a plaque is self-accelerating. Namely, once a plaque develops, it grows in an increasing rate with time and it does not stop growing. Within a part of arterial wall, older plaques grow faster than younger ones; thus old plaques are always bigger than new ones, resulting in an in-homogenous distribution of plaques. The oldest and the biggest plaque is the most threatening one in narrowing local vessel lumen; therefore the accelerated growing of plaques is a fatal factor in atherosclerosis.
The prevention and regression of atherosclerotic plaques: emerging treatments
Kalanuria AA, Nyquist P, Ling G
Vascular Health and Risk Management , 2012, DOI: http://dx.doi.org/10.2147/VHRM.S27764
Abstract: evention and regression of atherosclerotic plaques: emerging treatments Review (1904) Total Article Views Authors: Kalanuria AA, Nyquist P, Ling G Published Date September 2012 Volume 2012:8 Pages 549 - 561 DOI: http://dx.doi.org/10.2147/VHRM.S27764 Received: 07 May 2012 Accepted: 02 July 2012 Published: 25 September 2012 Atul Ashok Kalanuria,1 Paul Nyquist,1 Geoffrey Ling1,2 1Division of Neuro Critical Care, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, 2Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA Abstract: Occlusive vascular diseases, such as sudden coronary syndromes, stroke, and peripheral arterial disease, are a huge burden on the health care systems of developed and developing countries. Tremendous advances have been made over the last few decades in the diagnosis and treatment of atherosclerotic diseases. Intravascular ultrasound has been able to provide detailed information of plaque anatomy and has been used in several studies to assess outcomes. The presence of atherosclerosis disrupts the normal protective mechanism provided by the endothelium and this mechanism has been implicated in the pathophysiology of coronary artery disease and stroke. Efforts are being put into the prevention of atherosclerosis, which has been shown to begin in childhood. This paper reviews the pathophysiology of atherosclerosis and discusses the current options available for the prevention and reversal of plaque formation.
The prevention and regression of atherosclerotic plaques: emerging treatments  [cached]
Kalanuria AA,Nyquist P,Ling G
Vascular Health and Risk Management , 2012,
Abstract: Atul Ashok Kalanuria,1 Paul Nyquist,1 Geoffrey Ling1,21Division of Neuro Critical Care, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, 2Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USAAbstract: Occlusive vascular diseases, such as sudden coronary syndromes, stroke, and peripheral arterial disease, are a huge burden on the health care systems of developed and developing countries. Tremendous advances have been made over the last few decades in the diagnosis and treatment of atherosclerotic diseases. Intravascular ultrasound has been able to provide detailed information of plaque anatomy and has been used in several studies to assess outcomes. The presence of atherosclerosis disrupts the normal protective mechanism provided by the endothelium and this mechanism has been implicated in the pathophysiology of coronary artery disease and stroke. Efforts are being put into the prevention of atherosclerosis, which has been shown to begin in childhood. This paper reviews the pathophysiology of atherosclerosis and discusses the current options available for the prevention and reversal of plaque formation.Keywords: cardiovascular, atherosclerotic disease, endothelium, plaque, reversal, coronary artery disease, stroke
Adiponectin-coated nanoparticles for enhanced imaging of atherosclerotic plaques  [cached]
Almer G,Wernig K,Saba-Lepek M,Haj-Yahya S
International Journal of Nanomedicine , 2011,
Abstract: Gunter Almer1,6, Karin Wernig2, Matthias Saba-Lepek3, Samih Haj-Yahya1, Johannes Rattenberger4, Julian Wagner4, Kerstin Gradauer3, Daniela Frascione3, Georg Pabst3, Gerd Leitinger5, Harald Mangge1, Andreas Zimmer2, Ruth Prassl31Clinical Institute of Medical and Chemical Laboratory Diagnostics, 2Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, University of Graz, 3Institute of Biophysics and Nanosystems Research, Austrian Academy of Science, 4Institute for Electron Microscopy and Fine Structure Research, Graz University of Technology, 5Institute of Cell Biology, Histology and Embryology, Medical University of Graz, 6Center for Medical Research, Medical University of Graz, AustriaBackground: Atherosclerosis is a leading cause of mortality in the Western world, and plaque diagnosis is still a challenge in cardiovascular medicine. The main focus of this study was to make atherosclerotic plaques visible using targeted nanoparticles for improved imaging. Today various biomarkers are known to be involved in the pathophysiologic scenario of atherosclerotic plaques. One promising new candidate is the globular domain of the adipocytokine adiponectin (gAd), which was used as a targeting sequence in this study.Methods: gAd was coupled to two different types of nanoparticles, namely protamine-oligonucleotide nanoparticles, known as proticles, and sterically stabilized liposomes. Both gAd-targeted nanoparticles were investigated for their potency to characterize critical scenarios within early and advanced atherosclerotic plaque lesions using an atherosclerotic mouse model. Aortic tissue from wild type and apolipoprotein E-deficient mice, both fed a high-fat diet, were stained with either fluorescent-labeled gAd or gAd-coupled nanoparticles. Ex vivo imaging was performed using confocal laser scanning microscopy.Results: gAd-targeted sterically stabilized liposomes generated a strong signal by accumulating at the surface of atherosclerotic plaques, while gAd-targeted proticles became internalized and showed more spotted plaque staining.Conclusion: Our results offer a promising perspective for enhanced in vivo imaging using gAd-targeted nanoparticles. By means of nanoparticles, a higher payload of signal emitting molecules could be transported to atherosclerotic plaques. Additionally, the opportunity is opened up to visualize different regions in the plaque scenario, depending on the nature of the nanoparticle used.Keywords: adiponectin, nanoparticles, proticles, liposomes, molecular imaging, atherosclerosis
Multicolor fluorescence technique to detect apoptotic cells in advanced coronary atherosclerotic plaques  [cached]
C Soldani,AI Scovassi,U Canosi,E Bramucci
European Journal of Histochemistry , 2005, DOI: 10.4081/926
Abstract: Apoptosis occurring in atherosclerotic lesions has been suggested to be involved in the evolution and the structural stability of the plaques. It is still a matter of debate whether apoptosis mainly involves vascular smooth muscle cells (vSMCs) in the fibrous tissue or inflammatory (namely foam) cells, thus preferentially affecting the cell-poor lipid core of the atherosclerotic plaques. The aim of the present investigation was to detect the presence of apoptotic cells and to estimate their percentage in a series of atherosclerotic plaques obtained either by autopsy or during surgical atherectomy. Apoptotic cells were identified on paraffinembedded sections on the basis of cell nuclear morphology after DNA staining and/or by cytochemical reactions (TUNEL assay, immunodetection of the proteolytic poly (ADP-ribose) polymerase-1 [PARP-1] fragment); biochemical procedures (identifying DNA fragmentation or PARP-1 proteolysis) were also used. Indirect immunofluorescence techniques were performed to label specific antigens for either vSMCs or macrophages (i.e., the cells which are most likely prone to apoptosis in atherosclerotic lesions): the proper selection of fluorochrome labeling allowed the simultaneous detection of the cell phenotype and the apoptotic characteristics, by multicolor fluorescence techniques. Apoptotic cells proved to be less than 5% of the whole cell population, in atherosclerotic plaque sections: this is, in fact, a too low cell fraction to be detected by widely used biochemical methods, such as agarose gel electrophoresis of low-molecular-weight DNA or Western-blot analysis of PARP-1 degradation. Most apoptotic cells were of macrophage origin, and clustered in the tunica media, near or within the lipid-rich core; only a few TUNEL-positive cells were labeled for antigens specific for vSMCs. These results confirm that, among the cell populations in atherosclerotic plaques, macrophage foam-cells are preferentially involved in apoptosis. Their death may decrease the cell number in the lipid core and generate a possibly defective apoptotic clearance: the resulting release of matrix-degrading enzymes could contribute to weakening the fibrous cap and promote the plaque rupture with the risk of acute ischemic events, while increasing the thrombogenic pultaceous pool of the plaque core.
Adiponectin-coated nanoparticles for enhanced imaging of atherosclerotic plaques
Almer G, Wernig K, Saba-Lepek M, Haj-Yahya S, Rattenberger J, Wagner J, Gradauer K, Frascione D, Pabst G, Leitinger G, Mangge H, Zimmer A, Prassl R
International Journal of Nanomedicine , 2011, DOI: http://dx.doi.org/10.2147/IJN.S18739
Abstract: diponectin-coated nanoparticles for enhanced imaging of atherosclerotic plaques Original Research (4558) Total Article Views Authors: Almer G, Wernig K, Saba-Lepek M, Haj-Yahya S, Rattenberger J, Wagner J, Gradauer K, Frascione D, Pabst G, Leitinger G, Mangge H, Zimmer A, Prassl R Published Date June 2011 Volume 2011:6 Pages 1279 - 1290 DOI: http://dx.doi.org/10.2147/IJN.S18739 Gunter Almer1,6, Karin Wernig2, Matthias Saba-Lepek3, Samih Haj-Yahya1, Johannes Rattenberger4, Julian Wagner4, Kerstin Gradauer3, Daniela Frascione3, Georg Pabst3, Gerd Leitinger5, Harald Mangge1, Andreas Zimmer2, Ruth Prassl3 1Clinical Institute of Medical and Chemical Laboratory Diagnostics, 2Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, University of Graz, 3Institute of Biophysics and Nanosystems Research, Austrian Academy of Science, 4Institute for Electron Microscopy and Fine Structure Research, Graz University of Technology, 5Institute of Cell Biology, Histology and Embryology, Medical University of Graz, 6Center for Medical Research, Medical University of Graz, Austria Background: Atherosclerosis is a leading cause of mortality in the Western world, and plaque diagnosis is still a challenge in cardiovascular medicine. The main focus of this study was to make atherosclerotic plaques visible using targeted nanoparticles for improved imaging. Today various biomarkers are known to be involved in the pathophysiologic scenario of atherosclerotic plaques. One promising new candidate is the globular domain of the adipocytokine adiponectin (gAd), which was used as a targeting sequence in this study. Methods: gAd was coupled to two different types of nanoparticles, namely protamine-oligonucleotide nanoparticles, known as proticles, and sterically stabilized liposomes. Both gAd-targeted nanoparticles were investigated for their potency to characterize critical scenarios within early and advanced atherosclerotic plaque lesions using an atherosclerotic mouse model. Aortic tissue from wild type and apolipoprotein E-deficient mice, both fed a high-fat diet, were stained with either fluorescent-labeled gAd or gAd-coupled nanoparticles. Ex vivo imaging was performed using confocal laser scanning microscopy. Results: gAd-targeted sterically stabilized liposomes generated a strong signal by accumulating at the surface of atherosclerotic plaques, while gAd-targeted proticles became internalized and showed more spotted plaque staining. Conclusion: Our results offer a promising perspective for enhanced in vivo imaging using gAd-targeted nanoparticles. By means of nanoparticles, a higher payload of signal emitting molecules could be transported to atherosclerotic plaques. Additionally, the opportunity is opened up to visualize different regions in the plaque scenario, depending on the nature of the nanoparticle used.
Quantitative Analysis of Monocyte Subpopulations in Murine Atherosclerotic Plaques by Multiphoton Microscopy  [PDF]
Abigail S. Haka, Stephane Potteaux, Haley Fraser, Gwendalyn J. Randolph, Frederick R. Maxfield
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044823
Abstract: The progressive accumulation of monocyte-derived cells in the atherosclerotic plaque is a hallmark of atherosclerosis. However, it is now appreciated that monocytes represent a heterogeneous circulating population of cells that differ in functionality. New approaches are needed to investigate the role of monocyte subpopulations in atherosclerosis since a detailed understanding of their differential mobilization, recruitment, survival and emigration during atherogenesis is of particular importance for development of successful therapeutic strategies. We present a novel methodology for the in vivo examination of monocyte subpopulations in mouse models of atherosclerosis. This approach combines cellular labeling by fluorescent beads with multiphoton microscopy to visualize and monitor monocyte subpopulations in living animals. First, we show that multiphoton microscopy is an accurate and timesaving technique to analyze monocyte subpopulation trafficking and localization in plaques in excised tissues. Next, we demonstrate that multiphoton microscopy can be used to monitor monocyte subpopulation trafficking in atherosclerotic plaques in living animals. This novel methodology should have broad applications and facilitate new insights into the pathogenesis of atherosclerosis and other inflammatory diseases.
Adipose Tissue-Specific Deletion of 12/15-Lipoxygenase Protects Mice from the Consequences of a High-Fat Diet  [PDF]
Banumathi K. Cole,Margaret A. Morris,Wojciech J. Grzesik,Kendall A. Leone,Jerry L. Nadler
Mediators of Inflammation , 2012, DOI: 10.1155/2012/851798
Abstract: Type 2 diabetes is associated with obesity, insulin resistance, and inflammation in adipose tissue. 12/15-Lipoxygenase (12/15-LO) generates proinflammatory lipid mediators, which induce inflammation in adipose tissue. Therefore we investigated the role of 12/15-LO activity in mouse white adipose tissue in promoting obesity-induced local and systemic inflammatory consequences. We generated a mouse model for fat-specific deletion of 12/15-LO, aP2-Cre; 12/15-LOloxP/loxP, which we call ad-12/15-LO mice, and placed wild-type controls and ad-12/15-LO mice on a high-fat diet for 16 weeks and examined obesity-induced inflammation and insulin resistance. High-fat diet-fed ad-12/15-LO exhibited improved fasting glucose levels and glucose metabolism, and epididymal adipose tissue from these mice exhibited reduced inflammation and macrophage infiltration compared to wild-type mice. Furthermore, fat-specific deletion of 12/15-LO led to decreased peripheral pancreatic islet inflammation with enlarged pancreatic islets when mice were fed the high-fat diet compared to wild-type mice. These results suggest an interesting crosstalk between 12/15-LO expression in adipose tissue and inflammation in pancreatic islets. Therefore, deletion of 12/15-LO in adipose tissue can offer local and systemic protection from obesity-induced consequences, and blocking 12/15-LO activity in adipose tissue may be a novel therapeutic target in the treatment of type 2 diabetes. 1. Introduction Obesity is a rising worldwide epidemic affecting approximately one-third of adults [1]. Obesity is characterized by a persistent exposure to excess nutrients that leads to visceral adiposity and hyperlipidemia, promoting chronic inflammation, insulin resistance, and endoplasmic reticulum stress [2, 3]. This promotes the development of adipocyte dysfunction and systemic decline, including damage to the pancreas, liver, and vascular tissue. Therefore obesity predisposes individuals to the development of type 2 diabetes and cardiovascular disease. Increasing evidence from our lab suggests that the 12/15-lipoxygenase (12/15-LO) enzyme plays a critical role in promoting adipocyte dysfunction. 12/15-LO oxygenates polyunsaturated fatty acids to generate many proinflammatory lipid mediators (reviewed in [4]). 12/15-LO is largely involved in metabolizing arachidonic acid to form 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and linoleic acid to form 13-hydroperoxyoctadecadienoic acid (13-HPODE), which are further oxidized to 12-hydroxyeicosatetraenoic acid (12(S)-HETE) and 13-hydroxyoctadecadienoic acid
Association between Human Plasma Chondroitin Sulfate Isomers and Carotid Atherosclerotic Plaques  [PDF]
Elisabetta Zinellu,Antonio Junior Lepedda,Antonio Cigliano,Salvatore Pisanu,Angelo Zinellu,Ciriaco Carru,Pietro Paolo Bacciu,Franco Piredda,Anna Guarino,Rita Spirito,Marilena Formato
Biochemistry Research International , 2012, DOI: 10.1155/2012/281284
Abstract: Several studies have evidenced variations in plasma glycosaminoglycans content in physiological and pathological conditions. In normal human plasma GAGs are present mainly as undersulfated chondroitin sulfate (CS). The aim of the present study was to evaluate possible correlations between plasma CS level/structure and the presence/typology of carotid atherosclerotic lesion. Plasma CS was purified from 46 control subjects and 47 patients undergoing carotid endarterectomy showing either a soft or a hard plaque. The concentration and structural characteristics of plasma CS were assessed by capillary electrophoresis of constituent unsaturated fluorophore-labeled disaccharides. Results showed that the concentration of total CS isomers was increased by 21.4% (<0.01) in plasma of patients, due to a significant increase of undersulfated CS. Consequently, in patients the plasma CS charge density was significantly reduced with respect to that of controls. After sorting for plaque typology, we found that patients with soft plaques and those with hard ones differently contribute to the observed changes. In plasma from patients with soft plaques, the increase in CS content was not associated with modifications of its sulfation pattern. On the contrary, the presence of hard plaques was associated with CS sulfation pattern modifications in presence of quite normal total CS isomers levels. These results suggest that the plasma CS content and structure could be related to the presence and the typology of atherosclerotic plaque and could provide a useful diagnostic tool, as well as information on the molecular mechanisms responsible for plaque instability.
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