Kamp, A.W.M. van der http://repub.eur.nl/res/aut/12716/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png RePub, Erasmus University Rotterdam http://repub.eur.nl Increased risk of atherosclerosis by elevated plasma levels of phospholipid transfer protein. (Article) http://repub.eur.nl/res/pub/13113/ 2002-12-13T00:00:00Z Plasma phospholipid transfer protein (PLTP) is thought to be involved in the remodeling of high density lipoproteins (HDL), which are atheroprotective. It is also involved in the metabolism of very low density lipoproteins (VLDL). Hence, PLTP is thought to be an important factor in lipoprotein metabolism and the development of atherosclerosis. We have overexpressed PLTP in mice heterozygous for the low density lipoprotein (LDL) receptor, a model for atherosclerosis. We show that increased PLTP activity results in a dose-dependent decrease in HDL, and a moderate stimulation of VLDL secretion (</=1.5-fold). The mice were given a high fat, high cholesterol diet, which resulted in hypercholesterolemia in all animals. HDL concentrations were dramatically reduced in PLTP-overexpressing animals when compared with LDL receptor controls, whereas VLDL + LDL cholesterol levels were identical. Susceptibility to atherosclerosis was increased in a PLTP dose-responsive manner. We conclude that PLTP increases susceptibility to atherosclerosis by lowering HDL concentrations, and therefore we suggest that an increase in PLTP is a novel, long term risk factor for atherosclerosis in humans. Human plasma phospholipid transfer protein increases the antiatherogenic potential of high density lipoproteins in transgenic mice (Article) http://repub.eur.nl/res/pub/9314/ 2000-01-01T00:00:00Z 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. A Gp96/GRP94 is a putative high density lipoprotein-binding protein in liver. (Article) http://repub.eur.nl/res/pub/2588/ 1999-03-25T00:00:00Z We have previously shown that three high density lipoproteins (HDL)-binding proteins in liver, of 90, 110 and 180 kDa, are structurally related. In this study, these proteins are identified as gp96/GRP94. This protein is known to occur as a homodimer and has a dual subcellular localization: it is both an endoplasmic reticulum resident protein, where it is supposed to act as a chaperonin, and a plasma membrane protein, whose significance is unknown. In ultrastructural studies the plasma membrane localization of the homodimeric form was verified. The 90-kDa protein was abundantly present at the membranes of the endosomal/lysosomal vesicles as well as at the apical hepatocyte membranes, comprising the bile canaliculi. The monomeric protein is scarcely present at the basolateral membrane of the hepatocytes, but could be demonstrated in coated pits, suggesting involvement in receptor-mediated endocytosis. Labeling of the endoplasmic reticulum was virtually absent. Gp96/GRP94 was transiently expressed in COS-1 cells. However, the expressed protein was exclusively localized in the endoplasmic reticulum. Transfection with constructs in which the C-terminal KDEL sequence had been deleted, resulted in plasma membrane localized expression of protein, but only in an extremely low percentage of cells. In order to evaluate the HDL-binding capacities of this protein, stably transfected cells were generated, using several cell types. It appeared to be difficult to obtain a prolonged high level expression of gp96. In these cases, however, a marked increase of HDL-binding activity compared with the control cells could be observed. Sterilization and preservation for aortic-valve transplantation (Doctoral Thesis) http://repub.eur.nl/res/pub/26842/ 1976-06-23T00:00:00Z Recent advances in modern technology1 expertise and surgical enterprise hove contributed to the solution of may problems in the field of cardiovascular and thoracic surgery. Among these the surgical treatment of heart-valvedysfunctionby valve replacement has become possible (Murray, 1956; Ross, 1962; Starr and Edwards, 1961; Barrett-Boyes, 1964). Today transplantation of valves is an accepted surgical treatment next to corrective valve surgery and conservative therapy in the management of heart-valve disease. Heart-valve replacement becomes a necessity in case of congenital or aquired stenosis or insufficiency, if conservative treatment cannot prevent a progression of the lesions. In the decision for valve replacement the degree of invalidity experienced by ti-e patient is a major factor together with myocardial performance, No valve currently available for valve replacement fulfils the criteria for an ideal valve.