7 research outputs found
High Density Lipoprotein-Binding Proteins in Liver
In one of the oldest civilizations we know, that of ancient Egypt, thoughts
about the heart reflected a certain duality. On the one hand, the heart was
associated with concepts like virtue, or soul. A central passage in the Book
of the Dead of the ancient Egyptians is the description and illustration of the
weighing of the soul (Fig. 1). The heart of the diseased was put on a pair of
scales and balanced against the hieroglyphic symbol of virtue, the feather
maat. If the ibis god of scribes, Thot, could register a favourable verdict, the
dead man or woman was presented to the god of the dead, Osiris, and was
allowed entrance into the world of the dead. If not, the heart was devoured
by a horrifying beast, which event was described as the
Elevation of plasma phospholipid transfer protein in transgenic mice increases VLDL secretion
Two lipid transfer proteins are active in human plasma, cholesteryl ester
transfer protein (CETP), and phospholipid transfer protein (PLTP). Mice by
nature do not express CETP. Additional inactivation of the PLTP gene
resulted in reduced secretion of VLDL and subsequently in decreased
susceptibility to diet-induced atherosclerosis. The aim of this study is
to assess possible effects of differences in PLTP expression on VLDL
secretion in mice that are proficient in CETP and PLTP. We compared human
CETP transgenic (huCETPtg) mice with mice expressing both human lipid
transfer proteins (huCETPtg/huPLTPtg). Plasma cholesterol in huCETPtg mice
was 1.5-fold higher compared with huCETPtg/huPLTPtg mice (P < 0.001). This
difference was mostly due to a lower HDL level in the huCETPtg/huPLTPtg
mice, which subsequently could lead to the somewhat decreased CETP
activity and concentration that was found in huCETPtg/huPLTPtg mice (P <
0.05). PLTP activity was 2.8-fold increased in these animals (P < 0.001).
The human PLTP concentration was 5 microg/ml. Moderate overexpression of
PLTP resulted in a 1.5-fold higher VLDL secretion compared with huCETPtg
mice (P < 0.05). The composition of nascent VLDL was similar in both
strains. These results indicate that elevated PLTP activity in huCETPtg
mice results in an increase in VLDL secretion. In addition, PLTP
overexpression decreases plasma HDL cholesterol as well as CETP
Evaluation of phospholipid transfer protein and cholesteryl ester transfer protein as contributors to the generation of pre beta-high-density lipoproteins
High-density lipoproteins (HDLs) are considered anti-atherogenic because
they mediate peripheral cell cholesterol transport to the liver for
excretion and degradation. An important step in this reverse
cholesterol-transport pathway is the uptake of cellular cholesterol by a
specific subclass of small, lipid-poor apolipoprotein A-I particles
designated pre beta-HDL. The two lipid-transfer proteins present in human
plasma, cholesteryl ester transfer protein (CETP) and phospholipid
transfer protein (PLTP), have both been implicated in the formation of pre
beta-HDL. In order to investigate the relative contribution of each of
these proteins, we used transgenic mouse models. Comparisons were made
between human CETP transgenic mice (huCETPtg), human PLTP transgenic mice
(huPLTPtg) and mice transgenic for both lipid-transfer proteins
(huCETPtg/huPLTPtg). These animals showed elevated plasma levels of CETP
activity, PLTP activity or both activities, respectively. We evaluated the
generation of pre beta-HDL in mouse plasma by immunoblotting and crossed
immuno-electrophoresis. Generation of pre beta-HDL was equal in huCETPtg
and wild-type mice. In contrast, in huPLTPtg and huCETPtg/huPLTPtg mice,
pre beta-HDL generation was 3-fold higher than in plasma from either
wild-type or huCETPtg mice. Our findings demonstrate that, of the two
plasma lipid-transfer proteins, PLTP rather than CETP is responsible for
the generation of pre beta-HDL. These data support the hypothesis of a
role for PLTP in the initial stage of reverse cholesterol transport
Human plasma phospholipid transfer protein increases the antiatherogenic potential of high density lipoproteins in transgenic mice
Plasma phospholipid transfer protein (PLTP) transfers phospholipids
between lipoprotein particles and alters high density lipoprotein (HDL)
subfraction patterns in vitro, but its physiological function is poorly
understood. Transgenic mice that overexpress human PLTP were generated.
Compared with wild-type mice, these mice show a 2.5- to 4.5-fold increase
in PLTP activity in plasma. This results in a 30% to 40% decrease of
plasma levels of HDL cholesterol. Incubation of plasma from transgenic
animals at 37 degrees C reveals a 2- to 3-fold increase in the formation
of pre-beta-HDL compared with plasma from wild-type mice. Although
pre-beta-HDL is normally a minor subfraction of HDL, it is known to be a
very efficient acceptor of peripheral cell cholesterol and a key mediator
in reverse cholesterol transport. Further experiments show that plasma
from transgenic animals is much more efficient in preventing the
accumulation of intracellular cholesterol in macrophages than plasma from
wild-type mice, despite lower total HDL concentrations. It is concluded
that PLTP can act as an antiatherogenic factor preventing cellular
cholesterol overload by generation of pre-beta-HDL
Acute elevation of plasma PLTP activity strongly increases pre-existing atherosclerosis
Objective - A transgenic mouse model was generated that allows conditional expression of human PLTP, based on the tetracycline-responsive gene system, to study the effects of an acute increase in plasma PLTP activity as may occur in inflammation. Methods and Results - The effects of an acute elevation of plasma PLTP activity on the metabolism of apolipoprotein B-containing lipoproteins and on diet-induced pre-existing atherosclerosis were determined in mice displaying a humanized lipoprotein profile (low-density lipoprotein receptor knockout background). Induced expression of PLTP strongly increases plasma VLDL levels in LDL receptor knockout mice, whereas VLDL secretion is not affected. The elevation in plasma triglyceride levels is explained by a PLTP-dependent inhibition of VLDL catabolism, which is caused, at least partly, by a decreased lipoprotein lipase activity. Together with the decreased plasma HDL levels, the acutely increased PLTP expression results in a highly atherogenic lipoprotein profile. Induction of PLTP expression leads to a further increase in size of pre-existing atherosclerotic lesions, even on a chow diet. In addition, the lesions contain more macrophages and less collagen relative to controls, suggesting a less stable lesion phenotype. Conclusion - In conclusion, acute elevation of PLTP activity destabilizes atherosclerotic lesions and aggravates pre-existing atherosclerosis
Shear stress affects the intracellular distribution of eNOS: Direct demonstration by a novel in vivo technique
The focal location of atherosclerosis in the vascular tree is correlated with local variations in shear stress. We developed a method to induce defined variations in shear stress in a straight vessel segment of a mouse. To this end, a cylinder with a tapered lumen was placed around the carotid artery, inducing a high shear stress field. Concomitantly, regions of low shear stress and oscillatory shear stress were created upstream and downstream of the device, respectively. This device was used in mice transgenic for an eNOS3GFP fusion gene. We observed a strong induction of endothelial nitric oxide synthase-green fluorescent protein (eNOS-GFP) mRNA expression in the high shear stress region compared with the other regions (P < .05). Quantification of eNOS-GFP fluorescence or of immunoreactivity to the Golgi complex or to platelet endothelial cell adhesion molecule 1 (PECAM-1) showed an increase in the high shear stress region (P < .05) compared with nontreated carotid arteries. Colocalization of eNOS-GFP with either the Golgi complex or PECAM-1 also responded to alterations of shear stress. In conclusion, we showed a direct response of mRNA and protein expression in vivo to induced variations of shear stress. This model provides the opportunity to study the relationship between shear stress alterations, gene expression, and atherosclerosis
Early exercise training normalizes myofilament function and attenuates left ventricular pump dysfunction in mice with a large myocardial infarction
The extent and mechanism of the cardiac benefit of early exercise training following myocardial infarction (MI) is incompletely understood, but may involve blunting of abnormalities in Ca-handling and myofilament function. Consequently, we investigated the effects of 8-weeks of voluntary exercise, started early after a large MI, on left ventricular (LV) remodeling and dysfunction in the mouse. Exercise had no effect on survival, MI size or LV dimensions, but improved LV fractional shortening from 8±1 to 12±1%, and LVdP/dtP30 from 5295±207 to 5794±207 mm Hg/s (both P<0.05), and reduced pulmonary congestion. These global effects of exercise were associated with normalization of the MI-induced increase in myofilament Ca-sensitivity (ΔpCa50=0.037). This effect of exercise was PKA-mediated and likely because of improved β1-adrenergic signaling, as suggested by the increased β1-adrenoceptor protein (48%) and cAMP levels (36%; all P<0.05). Exercise prevented the MI-induced decreased maximum force generating capacity of skinned cardiomyocytes (Fmax increased from 14.3±0.7 to 18.3±0.8 kN/mP<0.05), which was associated with enhanced shortening of unloaded intact cardiomyocytes (from 4.1±0.3 to 7.0±0.6%; P<0.05). Furthermore, exercise reduced diastolic Ca-concentrations (by ∼30%, P<0.05) despite the unchanged SERCA2a and PLB expression and PLB phosphorylation status. Importantly, exercise had no effect on Ca-transient amplitude, indicating that the improved LV and cardiomyocyte shortening were principally because of improved myofilament function. In conclusion, early exercise in mice after a large MI has no effect on LV remodeling, but attenuates global LV dysfunction. The latter can be explained by the exercise-induced improvement of myofilament function