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Abstract: Objective: Plasma phospholipid transfer protein (PLTP) plays a key role in lipoprotein metabolism. Its exact function in the development of atherosclerosis is still under debate however. We studied the effect of elevated PLTP expression in one of the most commonly used models of atherosclerosis, the ApoE deficient mouse. Methods: Experiment 1: Plasma PLTP activity, total cholesterol, HDL cholesterol and atherosclerosis development was measured in ApoE deficient mice with or without elevated expression of PLTP. Experiment 2: The same parameters were measured in ApoE deficient mice after bone marrow transplantation from wild type mice or mice with elevated PLTP expression. Experiment 3: Similar to experiment 2, but using donor mice with an ApoE deficient background. Results: Experiment 1: ApoE deficient mice have more than two times more atherosclerosis when overexpressing PLTP and a strongly decreased plasma level of HDL. Experiment 2: Bone marrow transplantation with ApoE proficient cells results in a strong reduction of plasma cholesterol in ApoE deficient acceptor mice. Still, elevated PLTP in bone marrow derived cells evoke a reduction of HDL cholesterol and increased atherosclerosis. Experiment 3: Bone marrow transplantation with ApoE deficient cells results in much higher cholesterol levels, but here too HDL cholesterol levels are reduced and atherosclerosis increased. Conclusion: In all the models with ApoE deficiency, elevated PLTP expression causes higher levels of diet-induced atherosclerosis coinciding with decreased plasma levels of HDL cholesterol. [Copyright &y& Elsevier]

Abstract: Angiotensin II (ATII)-mediated hypertension increases the risk for acute coronary events, which may be caused by augmented collagen degradation. Interstitial fibers of collagen type I in the plaque can be degraded by MMP8 and MMP13 specifically. Indeed high MMP8 levels have been correlated with ruptured plaques in patients. To study the contribution of ATII in plaque rupture, we evaluated its effect on MMP8 and MMP13 activity on the vulnerable lesions using an extravascular device that induces regions of pro-atherogenic shear stress in the carotid arteries of ApoE KO mice. This triggers the growth of lesions with a “vulnerable” macrophage-rich phenotype (referred to as upstream lesions) and lesions with a “stable” fibrotic phenotype (referred to as downstream lesions). ATII administration increased mean blood pressure, and increased the incidence of intra-plaque hemorrhages (IPH) from 30% to 73% of the animals in the upstream segments. The area of IPH was also increased by 5-fold. No IPHs were observed in the downstream lesions of the control group or the ATII group. In addition, ATII treatment doubled the size of upstream and downstream lesions. Upstream lesions in the ATII group were decreased in collagen content by 3-fold, contained 2-fold higher MMP8 and MMP13 levels, with a 2- and 3-fold increase in collagen type I degradation by MMP8 and MMP13 respectively compared to the upstream lesions in the control group. Gene expression analysis showed general increase in procollagens and TIMPs expression in response to ATII. However, ATII also decreased procollagen 5α3 expression in downstream lesions and decreased TIMP4 expression in upstream lesions. These data show that ATII promotes a “stable” fibrotic phenotype by inducing severe intra-plaque hemorrhages, characterized by increased degradation of interstitial collagen I via an MMP-mediated (MMP8 and MMP13) mechanism. [Copyright &y& Elsevier]

Abstract: Phospholipid transfer protein (PLTP) is a multifunctional protein synthesized by various cell types and secreted into the plasma. Plasma PLTP is able to transfer phospholipids between lipoproteins and modulate HDL particles. Mice with overexpression of human PLTP have an increased ability to generate preβ-HDL, reduced total HDL levels and an increased susceptibility to atherosclerosis. As the macrophage is a key component of the atherosclerotic lesion and an important site of PLTP expression, we investigated the role of systemic and peripheral PLTP in macrophage cholesterol efflux and reverse cholesterol transport (RCT) in vivo. We used an assay in which 3H-labelled cholesterol-loaded macrophages were injected intraperitoneally into recipient mice, and radioactivity was quantified in plasma, liver and faeces. Firstly, wild type macrophages were injected into wild type, PLTP transgenic (PLTPtg) and apoAI transgenic (apoAItg) mice. While plasma 3H-tracer levels in apoAItg mice were increased compared with wild type mice, they were reduced in PLTPtg mice. Moreover, overexpression of PLTP significantly decreased faecal 3H-tracer levels compared with wild type and apoAItg mice. Secondly, wild type mice were injected with peritoneal macrophages derived from PLTPtg or wild type mice. No significant difference in the amount of 3H-tracer in plasma, liver or faeces was found between the two groups of mice. Our findings demonstrate that macrophage cholesterol efflux and RCT to faeces is impaired in PLTP transgenic mice, and that elevation of macrophage-PLTP does not affect RCT, indicating that higher systemic PLTP levels may promote atherosclerosis development by decreasing the rate of macrophage RCT. [Copyright &y& Elsevier]

Abstract: Wall shear stress (WSS), the frictional force between blood and endothelium, is an important determinant of vascular function. It is generally assumed that WSS remains constant at a reference value of 15dyn/cm2. In a study of small rodents, we realized that this assumption could not be valid. This review presents an overview of recent studies in large and small animals where shear stress was measured, derived from velocity measurements or otherwise, in large vessels. The data show that large variations exist within a single species (human: variation of 2–16N/m2). Moreover, when we compared different species at the same location within the arterial tree, an inverse relationship between animal size and wall shear stress was noted. When we related WSS to diameter, a unique relationship was derived for all species studied. This relationship could not be described by the well-known r 3 law of Murray, but by the r 2 law introduced by Zamir et al. in 1972. In summary, by comparing data from the literature, we have shown that: (i) the assumption of a physiological WSS level of ∼15dyn/cm2 for all straight vessels in the arterial tree is incorrect; (ii) WSS is not constant throughout the vascular tree; (iii) WSS varies between species; (iv) WSS is inversely related to the vessel diameter. These data support an “r 2 law” rather than Murray''s r 3 law for the larger vessels in the arterial tree. [Copyright &y& Elsevier]

Recent studies indicate a role of atherosclerosis-like changes involved in the pathogenesis of aortic valve stenosis. Interestingly, one of the major advanced glycation end products (AGEs), N#x03B5;-(carboxymethyl)lysine (CML) has been related to the process of atherosclerosis in blood vessels. In the present study, we have analyzed the presence of CML in degenerative altered aortic valves with atherosclerosis-like changes, and in degenerated mitral valves without atherosclerosis-like changes, derived from patients suffering from acute rheumatism during childhood. Degenerated and non-degenerated valves were derived from autopsy or obtained during cardiac surgery. The presence of CML was examined by immunohistochemistry. CML was found on the endothelium and fibroblasts in control aortic and mitral valves. Minor differences in CML staining were observed between control and degeneratively affected mitral valves. In contrast, in degenerated aortic valves, CML accumulation was found in macrophages and on calcification sites, comparable to that in atherosclerotic arteries, while the presence of CML staining on the endothelium and fibroblasts was significantly less as compared with control aortic valves. Our data support the hypothesis that the process of degeneration of aortic valves resembles that of atherosclerosis in blood vessels. They suggest that CML also plays a role in the process of atherosclerosis in aortic valves. [Copyright &y& Elsevier]