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Title: Hemorheological abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia

Abstract

Severe hypertriglyceridemia (HTG) is a metabolic disturbance often seen in clinical practice. It is known to induce life-threatening acute pancreatitis, but its role in atherogenesis remains elusive. Hemorheological abnormality was thought to play an important role in pathogenesis of both pancreatitis and atherosclerosis. However, hemorheology in severe HTG was not well investigated. Recently, we established a severe HTG mouse model deficient in lipoprotein lipase (LPL) in which severe HTG was observed to cause a significant increase in plasma viscosity. Disturbances of erythrocytes were also documented, including decreased deformability, electrophoresis rate, and membrane fluidity, and increased osmotic fragility. Scanning electron microscopy demonstrated that most erythrocytes of LPL deficient mice deformed with protrusions, irregular appearances or indistinct concaves. Analysis of erythrocyte membrane lipids showed decreased cholesterol (Ch) and phospholipid (PL) contents but unaltered Ch/PL ratio. The changes of membrane lipids may be partially responsible for the hemorheological and morphologic abnormalities of erythrocytes. This study indicated that severe HTG could lead to significant impairment of hemorheology and this model may be useful in delineating the role of severe HTG in the pathogenesis of hyperlipidemic pancreatitis and atherosclerosis.

Authors:
 [1];  [2];  [1];  [1];  [1];  [3];  [3];  [4];  [5]
  1. Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing 100083 (China) and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education (China)
  2. Hemorheology Center, Department of Biophysics, Health Science Center, Peking University, Beijing 100083 (China)
  3. Department of Medical Genetics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver (Canada)
  4. Hemorheology Center, Department of Biophysics, Health Science Center, Peking University, Beijing 100083 (China). E-mail: rheol@bjmu.edu.cn
  5. Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing 100083 (China) and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education (China). E-mail: vangeorgeliu@gmail.com
Publication Date:
OSTI Identifier:
20798853
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 341; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2006.01.067; PII: S0006-291X(06)00155-0; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ARTERIOSCLEROSIS; CHOLESTEROL; ELECTROPHORESIS; ERYTHROCYTES; LIPASES; LIPOPROTEINS; MEMBRANES; MICE; PATHOGENESIS; PHOSPHOLIPIDS; SCANNING ELECTRON MICROSCOPY; VISCOSITY

Citation Formats

Zhao Tieqiang, Guo Jun, Li Hui, Huang Wei, Xian Xunde, Ross, Colin J.D., Hayden, Michael R., Wen Zongyao, and Liu George. Hemorheological abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2006.01.067.
Zhao Tieqiang, Guo Jun, Li Hui, Huang Wei, Xian Xunde, Ross, Colin J.D., Hayden, Michael R., Wen Zongyao, & Liu George. Hemorheological abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia. United States. doi:10.1016/j.bbrc.2006.01.067.
Zhao Tieqiang, Guo Jun, Li Hui, Huang Wei, Xian Xunde, Ross, Colin J.D., Hayden, Michael R., Wen Zongyao, and Liu George. Fri . "Hemorheological abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia". United States. doi:10.1016/j.bbrc.2006.01.067.
@article{osti_20798853,
title = {Hemorheological abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia},
author = {Zhao Tieqiang and Guo Jun and Li Hui and Huang Wei and Xian Xunde and Ross, Colin J.D. and Hayden, Michael R. and Wen Zongyao and Liu George},
abstractNote = {Severe hypertriglyceridemia (HTG) is a metabolic disturbance often seen in clinical practice. It is known to induce life-threatening acute pancreatitis, but its role in atherogenesis remains elusive. Hemorheological abnormality was thought to play an important role in pathogenesis of both pancreatitis and atherosclerosis. However, hemorheology in severe HTG was not well investigated. Recently, we established a severe HTG mouse model deficient in lipoprotein lipase (LPL) in which severe HTG was observed to cause a significant increase in plasma viscosity. Disturbances of erythrocytes were also documented, including decreased deformability, electrophoresis rate, and membrane fluidity, and increased osmotic fragility. Scanning electron microscopy demonstrated that most erythrocytes of LPL deficient mice deformed with protrusions, irregular appearances or indistinct concaves. Analysis of erythrocyte membrane lipids showed decreased cholesterol (Ch) and phospholipid (PL) contents but unaltered Ch/PL ratio. The changes of membrane lipids may be partially responsible for the hemorheological and morphologic abnormalities of erythrocytes. This study indicated that severe HTG could lead to significant impairment of hemorheology and this model may be useful in delineating the role of severe HTG in the pathogenesis of hyperlipidemic pancreatitis and atherosclerosis.},
doi = {10.1016/j.bbrc.2006.01.067},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 341,
place = {United States},
year = {Fri Mar 24 00:00:00 EST 2006},
month = {Fri Mar 24 00:00:00 EST 2006}
}
  • To explore how enzyme affinities and enzyme activities regulate hydrolysis of water-insoluble substrates, the authors compared hydrolysis of phospholipid-stabilized emulsions of medium-chain (MCT) versus long-chain triacylglycerols (LCT). Because substrate solubility at the emulsion surface might modulate rates of hydrolysis, the ability of egg yolk phosphatidylcholine to solubilize MCT was examined by NMR spectroscopy. Chemical shift measurements showed that 11 mol % of ({sup 13}C)carbonyl enriched trioctanoin was incorporated into phospholipid vesicles as a surface component. Line widths of trioctanoin surface peaks were half that of LCT, and relaxation times, T{sub 1}, were also shorter for trioctanoin, showing greater mobility formore » MCT in phospholipid. In assessing the effects of these differences in solubility on lipolysis, they found that both purified bovine milk lipoprotein lipase and human hepatic lipase hydrolyzed MCT at rates at least 2-fold higher than for LCT. Differences in affinity were also demonstrated in mixed incubations where increasing amounts of LCT emulsion resulted in decreased hydrolysis of MCT emulsions. These results suggest that despite lower enzyme affinity for MCT emulsions, shorter chain triacylglycerols are more readily hydrolyzed by lipoprotein and hepatic lipases than long-chain triacylglycerols because of greater MCT solubility and mobility at the emulsion-water interface.« less
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  • Highlights: ► P-selectin regulates leukocyte recruitment as an early stage event of atherogenesis. ► We developed an antibody-based molecular imaging probe targeting P-selectin for PET. ► This is the first report on successful PET imaging for delineation of P-selectin. ► P-selectin is a candidate target for atherosclerotic plaque imaging by clinical PET. -- Abstract: Background: Sensitive detection and qualitative analysis of atherosclerotic plaques are in high demand in cardiovascular clinical settings. The leukocyte–endothelial interaction mediated by an adhesion molecule P-selectin participates in arterial wall inflammation and atherosclerosis. Methods and results: A {sup 64}Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugated anti-P-selectin monoclonal antibody ({sup 64}Cu-DOTA-anti-P-selectinmore » mAb) probe was prepared by conjugating an anti-P-selectin monoclonal antibody with DOTA followed by {sup 64}Cu labeling. Thirty-six hours prior to PET and CT fusion imaging, 3 MBq of {sup 64}Cu-DOTA-anti-P-selectin mAb was intravenously injected into low density lipoprotein receptor-deficient Ldlr-/- mice. After a 180 min PET scan, autoradiography and biodistribution of {sup 64}Cu-DOTA-anti-P-selectin monoclonal antibody was examined using excised aortas. In Ldlr-/- mice fed with a high cholesterol diet for promotion of atherosclerotic plaque development, PET and CT fusion imaging revealed selective and prominent accumulation of the probe in the aortic root. Autoradiography of aortas that demonstrated probe uptake into atherosclerotic plaques was confirmed by Oil red O staining for lipid droplets. In Ldlr-/- mice fed with a chow diet to develop mild atherosclerotic plaques, probe accumulation was barely detectable in the aortic root on PET and CT fusion imaging. Probe biodistribution in aortas was 6.6-fold higher in Ldlr-/- mice fed with a high cholesterol diet than in those fed with a normal chow diet. {sup 64}Cu-DOTA-anti-P-selectin mAb accumulated selectively in aortic atherosclerotic plaques and was detectable by PET and CT fusion imaging in Ldlr-/- mice. Conclusions: P-selectin is a candidate target molecule for early-phase detection by PET and CT fusion imaging of atherosclerotic plaques.« less
  • No abstract prepared.
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