Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

Background: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings: We generated mouse Znf202 expression vectors, the functionality of which...

Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft thickening in hypercholesterolemic apolipoprotein E3-Leiden mice

Objective: Inflammatory responses to vascular injury are key events in vein graft disease and accelerated atherosclerosis, which may result in bypass failure. The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor (CCR)-2 pathway is hypothesized to play a central role. A murine model for vein graft disease was used to study the...

CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischemic symptoms

BACKGROUND - Chemokines play an important role in atherogenesis and in ischemic injury and repair; however, prospective data on individual chemokines in unstable angina pectoris (UAP) are scarce. Therefore, we assessed chemokine patterns in a prospective cohort of patients with UAP. METHODS AND RESULTS - Plasma samples of 54 patients with...

Local cre-mediated gene recombination in vascular smooth muscle cells in mice

Here we describe a means to conditionally modify genes at a predefined and localized region of the vasculature using a perivascular drug delivery device (PDD). A 4-hydroxytamoxifen (4-OHT)-eluting PDD was applied around the carotid or femoral artery of a mouse strain carrying both the tamoxifen-inducible and smooth muscle cell (SMC)-specific Cre...

Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death

p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle...

Efficient targeting of adenoviral vectors to integrin positive vascular cells utilizing a CAR-cyclic RGD linker protein

Vascular smooth muscle (VSMC) and endothelial cells (EC) are particularly resistant to infection by type 5 adenovirus (Ad) vectors. To overcome this limitation and target Ad vectors to ubiquitously expressed α Vβ3/5 integrins, we have generated a linker protein consisting of the extracellular domain of the coxsackie adenovirus receptor (CAR)...

Design and synthesis of novel N-acetylgalactosamine-terminated glycolipids for targeting of lipoproteins to the hepatic asialoglycoprotein receptor

A novel glycolipid has been prepared that contains a cluster glycoside with an unusually high affinity for the asialoglycoprotein receptor (ASGPr) and a bile acid moiety that mediates stable incorporation into lipidic particles. The glycolipid spontaneously associated with low-density lipoproteins (LDL) and high-density lipoproteins (HDL) within...

Induction of atherosclerotic plaque rupture in apolipoprotein E-/- mice after adenovirus-mediated transfer of p53

Background - The presence of the tumor-suppressor gene p53 in advanced atherosclerotic plaques and the sensitivity to p53-induced cell death of smooth muscle cells isolated from these plaques have fueled speculation about the role of p53 in lesion destabilization and plaque rupture. In this study, we describe a strategy to promote (thrombotic)...

Apolipoprotein E is resistant to intracellular degradation in vitro and in vivo. Evidence for retroendocytosis

Apolipoprotein E (apoE) is an important determinant for the uptake of triglyceride-rich lipoproteins and emulsions by the liver, but the intracellular pathway of apoE following particle internalization is poorly defined. In the present study, we investigated whether retroendocytosis is a unique feature of apoE as compared with apoB by studying...

Interaction of mutants of tissue-type plasminogen activator with liver cells: Effect of domain deletions

The fibrin-specific thrombolyticum tissue-type plasminogen activator (t-PA) has proven to be a potent drug in several clinical trials, but its clinical application is complicated by the rapid clearance of t-PA from the circulation. The rapid plasma clearance of t-PA results from the uptake of t-PA in the liver. t-PA consists of several domains...

Lysine-based cluster mannosides that inhibit ligand binding to the human mannose receptor at nanomolar concentration

In search of synthetic high affinity ligands for the mannose receptor, we synthesized a series of lysine-based oligomannosides containing two (M2L) to six (M6L5) terminal alpha-D-mannose groups that are connected with the backbone by flexible elongated spacers (16 Å). The synthesized cluster mannosides were all able to displace binding of...

Prolonged circulation of tissue-type plasminogen activator in vivo by blocking mannose receptor and low-density-lipoprotein receptor-related protein-mediated liver uptake;

Abstract