T-cadherin expression in cardiac allograft vasculopathy: bench to bedside translational investigation.

Background: Coronary allograft vasculopathy (CAV) is the major limiting factor for long term survival after heart transplantation. The aim of this study was to identify gene candidates implicated in human CAV using a rat aortic allograft model in tandem with microarrays and quantitative real time PCR (Q-PCR).

Methods: Rat abdominal aortas were isografted (5) or allografted (5) from Brown-Norway to Lewis rats and grafts were harvested after day 8, 25 and 60.

Investigation of low-dose ritonavir on human peripheral blood mononuclear cells using gene expression whole genome microarrays.

Ritonavir is a protease inhibitor associated with metabolic abnormalities and cardiovascular disease. We have investigated the effects of low-dose ritonavir treatment on gene expression in peripheral blood mononuclear cells (PBMC) of 10 healthy donors. Results using whole genome Illumina microarrays show that ritonavir modulates a number of genes implicated in lipid metabolism, inflammation and atherosclerosis.

Prevention of atherosclerosis in patients living with HIV.

Unlabelled: INVESTIGATIONAL PRODUCT: Rosuvastatin (Crestor; Astra Zeneca).

Active Ingredients: Rosuvastatin (5 mg).

Study Title: Prevention of Atherosclerosis in Patients Living with HIV.

CD36 is significantly correlated with adipophilin in human carotid lesions and inversely correlated with plasma ApoAI.

OxLDL uptake and cholesterol efflux inhibition in macrophages play a key role in atherosclerotic plaque formation, rupture, and thrombotic ischemia. This study investigates genes implicated in OxLDL uptake (CD36, SRA), cholesterol efflux inhibition (adipophilin, ADFP), and inflammatory recruitments of leukocytes (IL-8) in plaque lesion areas (PLAs) compared to nonplaque lesion areas (NPLAs) in human carotid endarterectomy specimens. Gene and protein expressions were assayed using quantitative PCR and quantitative immunohistochemistry.

CD36 N-terminal cytoplasmic domain is not required for the internalization of oxidized low-density lipoprotein.

The uptake of OxLDLs (oxidized low density lipoproteins) by CD36-expressing macrophages in the arterial intima and the subsequent 'foam cell' formation represents a crucial step in the initiation and development of atherosclerotic plaques. The present study has addressed the function of the CD36 N-terminal cytoplasmic domain in the binding and internalization of OxLDL. A selection of CD36 N-terminal cytoplasmic domain mutants were generated and stably expressed in HEK-293 (human embryonic kidney) cells.

Expression of VE-Cadherin in Peritubular Endothelial Cells during Acute Rejection after Human Renal Transplantation.

Genes involved in acute rejection (AR) after organ transplantation remain to be further elucidated. In a previous work we have demonstrated the under-expression of VE-Cadherin by endothelial cells (EC) in AR following murine and human heart transplantation. Serial sections from 15 human kidney Banff-graded transplant biopsies were examined for the presence of VE-Cadherin and CD34 staining by immunohistochemistry (no AR (n = 5), AR grade IA (n = 5), or AR grade IIA (n = 5)).

Screening of subtle copy number changes in Aicardi syndrome patients with a high resolution X chromosome array-CGH.

Aicardi syndrome (AIC) is an uncommon neurodevelopmental disorder affecting almost exclusively females. Chief features include infantile spasms, corpus callosal agenesis, and chorioretinal abnormalities. AIC is a sporadic disorder and hypothesized to be caused by heterozygous mutations in an X-linked gene but up to now without any defined candidate region on the X chromosome.

6A3-5/Osa2 is an early activated gene implicated in the control of vascular smooth muscle cell functions.

Vascular smooth muscle cells (VSMC) growth plays a key role in the pathophysiology of vascular diseases. However, the molecular mechanisms controlling gene transcription in VSMC remain poorly understood. We previously identified, by differential display, a new gene (6A3-5) overexpressed in proliferating rat VSMC.

CD36 and macrophages in atherosclerosis.

CD36 is a multi-ligand scavenger receptor present on the surface of a number of cells such as platelets, monocytes/macrophages, endothelial and smooth muscle cells. Monocyte/macrophage CD36 has been shown to play a critical role in the development of atherosclerotic lesions by its capacity to bind and endocytose oxidized low density lipoproteins (OxLDL), and it is implicated in the formation of foam cells. However, the significance of CD36 in atherosclerosis has recently been called into question by different studies, and therefore its exact role still needs to be clarified.

Statin therapy-evidence beyond lipid lowering contributing to plaque stability.

Primarily statin drugs inhibit hepatic 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is responsible for the reduction in circulating low-density lipoprotein (LDL) cholesterol. Several findings from recent research studies indicate that statins have multiple actions that favorably influence key factors involved in the atherogenic process. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity.

Reduced atherosclerotic lesion size in P-selectin deficient apolipoprotein E-knockout mice fed a chow but not a fat diet.

P-selectin. We investigated the role of P-selectin on the development of vascular lesions in an ApoE(-/-) male mice. Double-knockout (ApoE(-/-), P-selectin(-/-); DKO) were compared to single-knockout (ApoE(-/-); SKO) mice.

Identification, structural, and functional characterization of a new early gene (6A3-5, 7 kb): implication in the proliferation and differentiation of smooth muscle cells.

Arterial smooth muscle cells (SMCs) play a major role in atherosclerosis and restenosis. Differential display was used to compare transcription profiles of synthetic SMCs to proliferating rat cultured SMC line. An isolated cDNA band (6A3-5) was shown by northern (7 kb) to be upregulated in the proliferating cell line.

Platelet-leukocyte aggregates and derived microparticles in inflammation, vascular remodelling and thrombosis.

As a result of vascular injury, activated platelets will rapidly interact with circulating platelets, via membrane glycoprotein complex alphaIIbbeta3 (GPIIb-IIIa) and fibrinogen, to form a thrombus or a plug preventing fatal bleeding. In addition, platelets interacting with ruptured atherosclerotic plaques or with the surface of diseased vessels can aggregate and induce ischemia that prevents blood flow. However, increasing evidence has also shown that circulating platelets interact with leukocytes and endothelial cells, via specific adhesion molecules, in inflammation, vascular remodelling and thrombosis.

Ischemia induces early expression of a new transcription factor (6A3-5) in kidney vascular smooth muscle cells: studies in rat and human renal pathology.

Acute renal failure, characterized by rapid decline in glomerular filtration rate, is a major cause of morbidity and mortality. During the evolution of renal diseases chronic ischemia develops. Indeed, acute or chronic renal failure may occur as a result of renal ischemia, which induces cells to dedifferentiate, proliferate, or become apoptotic.

Current perspective on antithrombin drugs.

Thrombin is a multifunctional serine protease, which is involved in blood coagulation and thrombosis, inflammation and wound repair in tissue injury. Its role in the amelioration of inflammatory tissue injury has been investigated. Protease-activated cell surface receptors (PARs) when activated by thrombin result in the production of proinflammatory mediators.

A peptide (P2) derived from the variable heavy chain of an anti-P-selectin monoclonal antibody (LYP20) inhibits leucocyte adhesion to thrombin-activated platelets and endothelial cells.

P-selectin, a member of the selectin family of adhesion molecules, is present in endothelial Weibel-Palade bodies and platelet alpha-granules, and is rapidly expressed on their surface upon activation, resulting in leucocyte adhesion. LYP20 is a functional monoclonal antibody previously generated in our laboratory that binds with high affinity and specificity directed against P-selectin. This binding is largely imparted by the specific sequence of amino acids present on the hypervariable portions of the IgG chains.

CD36 mRNA and Protein Expression Levels Are Significantly Increased in the Heart and Testis of apoE Deficient Mice in Comparison to Wild Type (C57BL/6).

CD36, an 88kd-adhesion molecule, plays a major role as a scavenging receptor implicated in cellular lipid metabolism. Secretory mammary epithelium, microvasculature endothelium, adipocytes, smooth muscle cells, and platelets express CD36. In addition, CD36 expression is significantly enhanced in macrophages differentiating into foam cells.

The terminal six amino-acids of the carboxy cytoplasmic tail of CD36 contain a functional domain implicated in the binding and capture of oxidized low-density lipoprotein.

CD36, a major adhesion molecule expressed by monocytes/macrophages, plays a key role in the binding and internalization of oxidized low-density lipoprotein (OxLDL). This adhesion molecule, a member of an important scavenger receptor family, contains a very short C-terminal cytoplasmic tail that is known to induce intracellular signalling events. However, the domains on the cytoplasmic tail involved in such signal transduction are unknown.