The Experts below are selected from a list of 20607 Experts worldwide ranked by ideXlab platform

Robert F Hoyt - One of the best experts on this subject based on the ideXlab platform.

  • the atp binding cassette transporter a1 abca1 modulates the development of Aortic Atherosclerosis in c57bl 6 and apoe knockout mice
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Charles Joyce, Jamila Najibfruchart, Robert F Hoyt, Edward D Neufeld, Beverly Paigen, Boris Vaisman, Gilles Lambert, Alan T. Remaley, Donald S. Fredrickson
    Abstract:

    Abstract Identification of mutations in the ABCA1 transporter (ABCA1) as the genetic defect in Tangier disease has generated interest in modulating atherogenic risk by enhancing ABCA1 gene expression. To investigate the role of ABCA1 in atherogenesis, we analyzed diet-induced Atherosclerosis in transgenic mice overexpressing human ABCA1 (hABCA1-Tg) and spontaneous lesion formation in hABCA1-Tg × apoE-knockout (KO) mice. Overexpression of hABCA1 in C57BL/6 mice resulted in a unique anti-atherogenic profile characterized by decreased plasma cholesterol (63%), cholesteryl ester (63%), free cholesterol (67%), non-high density lipoprotein (HDL)-cholesterol (53%), and apolipoprotein (apo) B (64%) but markedly increased HDL-cholesterol (2.8-fold), apoA-I (2.2-fold), and apoE (2.8-fold) levels. These beneficial changes in the lipid profile led to significantly lower (65%) Aortic Atherosclerosis in hABCA1-Tg mice. In marked contrast, ABCA1 overexpression had a minimal effect on the plasma lipid profile of apoE-KO mice and resulted in a 2- to 2.6-fold increase in Aortic lesion area. These combined results indicate that overexpression of ABCA1 in C57BL/6 mice on a high cholesterol diet results in an atheroprotective lipoprotein profile and decreased Atherosclerosis, and thus provide previously undocumented in vivo evidence of an anti-atherogenic role for the ABCA1 transporter. In contrast, overexpression of ABCA1 in an apoE-KO background led to increased Atherosclerosis, further substantiating the important role of apoE in macrophage cholesterol metabolism and atherogenesis. In summary, these results establish that, in the presence of apoE, overexpression of ABCA1 modulates HDL as well as apoB-containing lipoprotein metabolism and reduces Atherosclerosis in vivo, and indicate that pharmacological agents that will increase ABCA1 expression may reduce atherogenic risk in humans.

  • cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces Aortic Atherosclerosis in lecithin cholesterol acyltransferase transgenic mice
    Journal of Biological Chemistry, 1999
    Co-Authors: Robert F Hoyt, Beverly Paigen, Boris Vaisman, Robert D Shamburek, Marcelo Amar, Bernhard Foger, Michael Chase, Jamila Fruchartnajib, Jorge Paiz, Christine Koch
    Abstract:

    Abstract Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced Atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (−39% and −13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of [3H]cholesteryl esters ([3H]CE) from HDL (fractional catabolic rate in days−1: LCAT-Tg = 3.7 ± 0.34, LCATxCETP-Tg = 6.1 ± 0.16, and controls = 6.4 ± 0.16) as well as the liver uptake of [3H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean Aortic lesion area was reduced by 41% in LCATxCETP-Tg (21.2 ± 2.0 μm2 × 103) compared with LCAT-Tg mice (35.7 ± 2.0 μm2 × 103;p < 0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver uptake of [3H]CE from LCAT-Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and Atherosclerosis in these animals. We conclude that CETP expression reduces Atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL-CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport.

  • cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces Aortic Atherosclerosis in lecithin cholesterol acyltransferase transgenic mice
    Journal of Biological Chemistry, 1999
    Co-Authors: Robert F Hoyt, Beverly Paigen, Boris Vaisman, Robert D Shamburek, Marcelo Amar, Bernhard Foger, Michael Chase, Jamila Fruchartnajib, Jorge Paiz, Christine A Koch
    Abstract:

    Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced Atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (-39% and -13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of [(3)H]cholesteryl esters ([(3)H]CE) from HDL (fractional catabolic rate in days(-1): LCAT-Tg = 3.7 +/- 0.34, LCATxCETP-Tg = 6.1 +/- 0.16, and controls = 6.4 +/- 0.16) as well as the liver uptake of [(3)H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean Aortic lesion area was reduced by 41% in LCATxCETP-Tg (21.2 +/- 2.0 micrometer(2) x 10(3)) compared with LCAT-Tg mice (35.7 +/- 2.0 micrometer(2) x 10(3); p < 0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver uptake of [(3)H]CE from LCAT-Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and Atherosclerosis in these animals. We conclude that CETP expression reduces Atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL-CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport.

Bernhard Foger - One of the best experts on this subject based on the ideXlab platform.

  • cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces Aortic Atherosclerosis in lecithin cholesterol acyltransferase transgenic mice
    Journal of Biological Chemistry, 1999
    Co-Authors: Robert F Hoyt, Beverly Paigen, Boris Vaisman, Robert D Shamburek, Marcelo Amar, Bernhard Foger, Michael Chase, Jamila Fruchartnajib, Jorge Paiz, Christine Koch
    Abstract:

    Abstract Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced Atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (−39% and −13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of [3H]cholesteryl esters ([3H]CE) from HDL (fractional catabolic rate in days−1: LCAT-Tg = 3.7 ± 0.34, LCATxCETP-Tg = 6.1 ± 0.16, and controls = 6.4 ± 0.16) as well as the liver uptake of [3H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean Aortic lesion area was reduced by 41% in LCATxCETP-Tg (21.2 ± 2.0 μm2 × 103) compared with LCAT-Tg mice (35.7 ± 2.0 μm2 × 103;p < 0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver uptake of [3H]CE from LCAT-Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and Atherosclerosis in these animals. We conclude that CETP expression reduces Atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL-CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport.

  • cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces Aortic Atherosclerosis in lecithin cholesterol acyltransferase transgenic mice
    Journal of Biological Chemistry, 1999
    Co-Authors: Robert F Hoyt, Beverly Paigen, Boris Vaisman, Robert D Shamburek, Marcelo Amar, Bernhard Foger, Michael Chase, Jamila Fruchartnajib, Jorge Paiz, Christine A Koch
    Abstract:

    Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced Atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (-39% and -13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of [(3)H]cholesteryl esters ([(3)H]CE) from HDL (fractional catabolic rate in days(-1): LCAT-Tg = 3.7 +/- 0.34, LCATxCETP-Tg = 6.1 +/- 0.16, and controls = 6.4 +/- 0.16) as well as the liver uptake of [(3)H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean Aortic lesion area was reduced by 41% in LCATxCETP-Tg (21.2 +/- 2.0 micrometer(2) x 10(3)) compared with LCAT-Tg mice (35.7 +/- 2.0 micrometer(2) x 10(3); p < 0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver uptake of [(3)H]CE from LCAT-Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and Atherosclerosis in these animals. We conclude that CETP expression reduces Atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL-CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport.

Warren J Manning - One of the best experts on this subject based on the ideXlab platform.

  • association of descending thoracic Aortic plaque with brain atrophy and white matter hyperintensities the framingham heart study
    Atherosclerosis, 2017
    Co-Authors: Hugo J Aparicio, Warren J Manning, Rodica E Petrea, Joseph M Massaro, Noriko Oyamamanabe, Alexa Beiser, Carlos S Kase, Ralph B Dagostino, Philip A Wolf, Ramachandran S Vasan
    Abstract:

    Abstract Background and aims Aortic Atherosclerosis is an aggregate marker of vascular risk factor exposure and has been associated with intracranial Atherosclerosis and stroke. We hypothesized that Atherosclerosis of the descending aorta (DAo) could be a risk marker for brain aging and injury. Methods We evaluated 1527 participants (mean age 59.9 years, 53.5% women) in the Framingham Offspring cohort who underwent both Aortic and brain MRI. Participants were free of clinical stroke, dementia, or other neurological illness at the time of axial MRI of the thoracic and abdominal DAo and subsequent brain MRI. We related the prevalence and burden of Aortic plaque to total cerebral brain volume (TCBV) and white matter hyperintensity volume (WMHV). An additional analysis compared incidence of stroke or TIA in participants with and without DAo plaques. Results Presence of thoracic DAo plaque (8%) was associated with decreased TCBV in sex-pooled analysis (−0.77, SE 0.25, p  = 0.002, equivalent to 4.5 years of aging) and with increased WMHV only in men (0.26, SE 0.12, p  = 0.032, equivalent to 6.5 years aging). We observed similar associations of DAo plaque burden with TCBV and WMHV. There were 43 strokes and 11 TIAs in prospective follow-up (median 7 years). Presence of DAo plaque was not associated with subsequent stroke or TIA. Conclusions In this cross-sectional community-based study, we found DAo plaque is associated with accelerated brain aging. These data underscore the potential implications of incidentally identified subclinical Aortic Atherosclerosis and question whether targeted intervention in these high risk individuals can modulate cognitive decline.

  • subclinical coronary and Aortic Atherosclerosis detected by magnetic resonance imaging in type 1 diabetes with and without diabetic nephropathy
    Circulation, 2006
    Co-Authors: Won Yong Kim, Rene M Botnar, Anne Sofie Astrup, Matthias Stuber, Lise Tarnow, Erling Falk, Cheryl Simonsen, Lotte Pietraszek, Peter Riis Hansen, Warren J Manning
    Abstract:

    Background— Patients with type 1 diabetes and nephropathy maintain an excess cardiovascular mortality compared with diabetic patients with normoalbuminuria. We sought to evaluate coronary and Aortic Atherosclerosis in a cohort of asymptomatic type 1 diabetic patients with and without diabetic nephropathy using cardiovascular magnetic resonance imaging. Methods and Results— In a cross-sectional study, 136 subjects with long-standing type 1 diabetes without symptoms or history of cardiovascular disease, including 63 patients (46%) with nephropathy and 73 patients with normoalbuminuria, underwent cardiovascular magnetic resonance imaging. All subjects underwent cardiac exercise testing and noninvasive tests for peripheral artery disease and autonomic neuropathy. Coronary artery stenoses were identified in 10% of subjects with nephropathy (versus 0% with normoalbuminuria; P=0.007). Coronary plaque burden, expressed as right coronary artery mean wall thickness (1.7±0.3 versus 1.3±0.2 mm; P<0.001) and maximum r...

  • age and sex distribution of subclinical Aortic Atherosclerosis a magnetic resonance imaging examination of the framingham heart study
    Arteriosclerosis Thrombosis and Vascular Biology, 2002
    Co-Authors: Farouc A Jaffer, Christopher J Odonnell, Martin G Larson, Stephen Kamwah Chan, Kraig V Kissinger, Michelle J Kupka, Carol J Salton, Rene M Botnar, Daniel Levy, Warren J Manning
    Abstract:

    Autopsy data demonstrate a correlation between subclinical Aortic Atherosclerosis and cardiovascular disease. Therefore, noninvasive cardiovascular magnetic resonance (CMR) of subclinical Atherosclerosis may provide a novel measure of cardiovascular risk, but it has not been applied to an asymptomatic population-based cohort to establish age- and sex-specific normative data. Participants in the Framingham Heart Study offspring cohort who were free of clinically apparent coronary disease were randomly sampled from strata of sex, quartiles of age, and quintiles of Framingham Coronary Risk Score. Subjects (n=318, aged 60±9 years, range 36 to 78 years, 51% women) underwent ECG-gated T2-weighted black-blood thoracoabdominal Aortic CMR scanning. CMR evidence of Aortic Atherosclerosis was noted in 38% of the women and 41% of the men. Plaque prevalence and all measures of plaque burden increased with age group and were greater in the abdomen than in the thorax for both sexes and across all age groups. In addition, the Framingham Coronary Risk Score was significantly correlated with all plaque prevalence and burden measures for women but only for men after age adjustment. These noninvasive CMR data extend the prior autopsy-based prevalence estimates of subclinical Atherosclerosis and may help to lay the foundation for future studies of risk stratification and treatment of affected individuals.

William Vandecker - One of the best experts on this subject based on the ideXlab platform.

  • association of carotid artery intima media thickness with complex Aortic Atherosclerosis in patients with recent stroke
    Angiology, 2002
    Co-Authors: Panayotis Fasseas, Emmanouil S Brilakis, Biana Leybishkis, Marc Cohen, Alexis B Sokil, Nelson M Wolf, Rose Lee Dorn, Andrew B Roberts, William Vandecker
    Abstract:

    This study was undertaken to determine whether carotid intima-media thickness can predict complex Aortic Atherosclerosis. A retrospective review was conducted of 64 consecutive patients who underwent transesophageal echocardiography and carotid ultrasonography for evaluation of recent ischemic stroke at MCP Hahnemann University, Medical College of Pennsylvania Hospital between January 1, 1999, and December 31, 1999. The mean age was 65 ± 14 years and 59% of the patients were women. Thirty-nine patients (61 %) had carotid Atherosclerosis (defined as an intima-media thickness ≥ 1 mm) and seven patients (11%) had complex Aortic Atherosclerosis (defined as the presence of protruding atheroma ≥4 mm thick, mobile atherosclerotic debris, or plaque ulceration in any Aortic segment by transesophageal echocardiography). Compared to patients without complex Aortic Atherosclerosis, patients with complex Aortic Atherosclerosis were more likely to have hypercholesterolemia (19% vs 57%, p = 0.05) and a carotid intima-me...

  • association of carotid artery intima media thickness with complex Aortic Atherosclerosis in patients with recent stroke
    Angiology, 2002
    Co-Authors: Panayotis Fasseas, Emmanouil S Brilakis, Biana Leybishkis, Marc Cohen, Alexis B Sokil, Nelson M Wolf, Rose Lee Dorn, Andrew B Roberts, William Vandecker
    Abstract:

    This study was undertaken to determine whether carotid intima-media thickness can predict complex Aortic Atherosclerosis. A retrospective review was conducted of 64 consecutive patients who underwent transesophageal echocardiography and carotid ultrasonography for evaluation of recent ischemic stroke at MCP Hahnemann University, Medical College of Pennsylvania Hospital between January 1, 1999, and December 31, 1999. The mean age was 65+/-14 years and 59% of the patients were women. Thirty-nine patients (61%) had carotid Atherosclerosis (defined as an intima-media thickness > or =1 mm) and seven patients (11%) had complex Aortic Atherosclerosis (defined as the presence of protruding atheroma > or =4 mm thick, mobile atherosclerotic debris, or plaque ulceration in any Aortic segment by transesophageal echocardiography). Compared to patients without complex Aortic Atherosclerosis, patients with complex Aortic Atherosclerosis were more likely to have hypercholesterolemia (19% vs 57%, p = 0.05) and a carotid intima-media thickness of 2 mm or greater (35% vs 86%, p = 0.02). A carotid intima-media thickness of 2 mm or more had 86% sensitivity, 65% specificity, 23% positive predictive value, 97% negative predictive value, 2.5 positive likelihood ratio, and 0.22 negative likelihood ratio for the diagnosis of complex Aortic Atherosclerosis. Carotid intimamedia thickness measurement can be used to noninvasively estimate the probability of complex Aortic Atherosclerosis. A carotid intima-media thickness less than 2 mm makes complex Aortic Atherosclerosis very unlikely.

Beverly Paigen - One of the best experts on this subject based on the ideXlab platform.

  • the atp binding cassette transporter a1 abca1 modulates the development of Aortic Atherosclerosis in c57bl 6 and apoe knockout mice
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Charles Joyce, Jamila Najibfruchart, Robert F Hoyt, Edward D Neufeld, Beverly Paigen, Boris Vaisman, Gilles Lambert, Alan T. Remaley, Donald S. Fredrickson
    Abstract:

    Abstract Identification of mutations in the ABCA1 transporter (ABCA1) as the genetic defect in Tangier disease has generated interest in modulating atherogenic risk by enhancing ABCA1 gene expression. To investigate the role of ABCA1 in atherogenesis, we analyzed diet-induced Atherosclerosis in transgenic mice overexpressing human ABCA1 (hABCA1-Tg) and spontaneous lesion formation in hABCA1-Tg × apoE-knockout (KO) mice. Overexpression of hABCA1 in C57BL/6 mice resulted in a unique anti-atherogenic profile characterized by decreased plasma cholesterol (63%), cholesteryl ester (63%), free cholesterol (67%), non-high density lipoprotein (HDL)-cholesterol (53%), and apolipoprotein (apo) B (64%) but markedly increased HDL-cholesterol (2.8-fold), apoA-I (2.2-fold), and apoE (2.8-fold) levels. These beneficial changes in the lipid profile led to significantly lower (65%) Aortic Atherosclerosis in hABCA1-Tg mice. In marked contrast, ABCA1 overexpression had a minimal effect on the plasma lipid profile of apoE-KO mice and resulted in a 2- to 2.6-fold increase in Aortic lesion area. These combined results indicate that overexpression of ABCA1 in C57BL/6 mice on a high cholesterol diet results in an atheroprotective lipoprotein profile and decreased Atherosclerosis, and thus provide previously undocumented in vivo evidence of an anti-atherogenic role for the ABCA1 transporter. In contrast, overexpression of ABCA1 in an apoE-KO background led to increased Atherosclerosis, further substantiating the important role of apoE in macrophage cholesterol metabolism and atherogenesis. In summary, these results establish that, in the presence of apoE, overexpression of ABCA1 modulates HDL as well as apoB-containing lipoprotein metabolism and reduces Atherosclerosis in vivo, and indicate that pharmacological agents that will increase ABCA1 expression may reduce atherogenic risk in humans.

  • cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces Aortic Atherosclerosis in lecithin cholesterol acyltransferase transgenic mice
    Journal of Biological Chemistry, 1999
    Co-Authors: Robert F Hoyt, Beverly Paigen, Boris Vaisman, Robert D Shamburek, Marcelo Amar, Bernhard Foger, Michael Chase, Jamila Fruchartnajib, Jorge Paiz, Christine Koch
    Abstract:

    Abstract Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced Atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (−39% and −13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of [3H]cholesteryl esters ([3H]CE) from HDL (fractional catabolic rate in days−1: LCAT-Tg = 3.7 ± 0.34, LCATxCETP-Tg = 6.1 ± 0.16, and controls = 6.4 ± 0.16) as well as the liver uptake of [3H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean Aortic lesion area was reduced by 41% in LCATxCETP-Tg (21.2 ± 2.0 μm2 × 103) compared with LCAT-Tg mice (35.7 ± 2.0 μm2 × 103;p < 0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver uptake of [3H]CE from LCAT-Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and Atherosclerosis in these animals. We conclude that CETP expression reduces Atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL-CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport.

  • cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces Aortic Atherosclerosis in lecithin cholesterol acyltransferase transgenic mice
    Journal of Biological Chemistry, 1999
    Co-Authors: Robert F Hoyt, Beverly Paigen, Boris Vaisman, Robert D Shamburek, Marcelo Amar, Bernhard Foger, Michael Chase, Jamila Fruchartnajib, Jorge Paiz, Christine A Koch
    Abstract:

    Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced Atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (-39% and -13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of [(3)H]cholesteryl esters ([(3)H]CE) from HDL (fractional catabolic rate in days(-1): LCAT-Tg = 3.7 +/- 0.34, LCATxCETP-Tg = 6.1 +/- 0.16, and controls = 6.4 +/- 0.16) as well as the liver uptake of [(3)H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean Aortic lesion area was reduced by 41% in LCATxCETP-Tg (21.2 +/- 2.0 micrometer(2) x 10(3)) compared with LCAT-Tg mice (35.7 +/- 2.0 micrometer(2) x 10(3); p < 0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver uptake of [(3)H]CE from LCAT-Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and Atherosclerosis in these animals. We conclude that CETP expression reduces Atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL-CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport.