No abstract

Our data provide pharmacological and genetic evidence that endogenous PARP1 is required for atherogenesis in vivo by increasing adhesion molecules with endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising therapeutic target in atherosclerosis.

Endothelial-specific LOX-1 overexpression enhanced aortic oxLDL levels, thereby favouring endothelial dysfunction, vascular inflammation and plaque formation. Thus, LOX-1 may serve as a novel therapeutic target for atherosclerosis.

No abstract

BNP is a marker of systolic left ventricular dysfunction (LVSD) and heart failure. To assess BNP for the detection of diastolic dysfunction in the general population, we examined 1678 subjects within an age-and sex-stratified survey (MONICA Augsburg). BNP was measured using a commercially available RIA (Shionogi).BNP increased in subjects with diastolic dysfunction (mean 20.3F4.7 pg/ml vs. control 9.6F0.5 pg/ml, pb0.001), but to a lesser extent than in subjects with LV hypertrophy (LVH, mean 37.3F49.1 pg/ml, pb0.001 vs. control) or LVSD (mean 76.2F23.2 pg/ml, pb0.001 vs. control). Individuals with sole diastolic abnormality displayed BNP concentrations at the control level (mean 9.7F1.7 pg/ ml). In univariate analysis, age, BMI, systolic blood pressure, left atrial size, LV mass index, diastolic dysfunction and EF displayed a significant correlation with BNP ( pb0.001). However, LV mass index displaced diastolic dysfunction as a significant predictor of BNP in multivariate analysis. Upon ROC analysis, sensitivity and specificity for the detection of diastolic dysfunction by BNP were only 61% and 55%, respectively. Nevertheless, a normal BNP test virtually excluded the presence of diastolic dysfunction and concomitant LVH (NPV 99.9%).Increased BNP concentrations in subjects with diastolic dysfunction are strongly related to LVH. Population-wide screening for diastolic dysfunction with BNP cannot be recommended although a normal BNP test usually excludes diastolic dysfunction and LV hypertrophy.

Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. Cardiovascular safety profiles of currently applied anti-angiogenic regimens should be determined to improve patient selection for therapy and allow close monitoring of patients at increased cardiovascular risk.

Background and Purpose-The pathophysiology of vascular lesions after balloon angioplasty remains poorly understood.A major limitation of most experimental studies in this regard is that injury was assessed in healthy arteries. Our aim was to study the effects of hypercholesterolemia in a mouse vascular injury model that mimics human balloon angioplasty. Methods-Carotid balloon distension was performed in wild-type (WT) mice on a normal diet (ND), in apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice on ND and in ApoE Ϫ/Ϫ mice fed a high cholesterol diet (CD). Results-Medial cell death (TUNEL) was elevated in all mice at 1 hour and 1 day after angioplasty without differences between the groups. We found enhanced intimal inflammation (%CD45-positive cells) and vascular cell adhesion molecule-1 expression at 7 days (PϽ0.05; nՆ4) as well as increased proliferation rates (BrdU-index) in ApoE Ϫ/Ϫ CD at 7 and 28 days postinjury (PϽ0.05; nՆ5). Four weeks after injury, these events led to enhanced neointima in ApoE

Background-Fas (CD95/Apo-1) ligand (FasL)-induced apoptosis in Fas-bearing cells is critically involved in modulating immune reactions and tissue repair. Apoptosis has also been described after mechanical vascular injury such as percutaneous coronary intervention. However, the relevance of cell death in this context of vascular repair remains unknown. Methods and Results-To determine whether FasL-induced apoptosis is causally related to neointimal lesion formation, we subjected FasL-deficient (generalized lymphoproliferative disorder [gld], C57BL/6J) and corresponding wild-type (WT) mice to carotid balloon distension injury, which induces marked endothelial denudation and medial cell death. FasL expression in WT mice was induced in injured vessels compared with untreated arteries (PϽ0.05; nϭ5). Conversely, absence of functional FasL in gld mice decreased medial and intimal apoptosis (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling [TUNEL] index) at 1 hour and 7 days after balloon injury (PϽ0.05; nϭ6). In addition, peritoneal macrophages isolated from gld mice showed no apoptosis and enhanced migration (PϽ0.05; nϭ4). In parallel, we observed increased balloon-induced macrophage infiltrations (anti-CD68) in injured arteries of FasL-deficient animals (PϽ0.05; nϭ6). Together with enhanced proliferation (bromodeoxyuridine index; PϽ0.05), these events resulted in a further increase in medial and neointimal cells (PϽ0.01; nϭ8) with thickened neointima in gld mice (intima/media ratio, ϫ3.8 of WT; PϽ0.01). Conclusions-Our data identify proapoptotic and antiinflammatory effects of endogenous FasL as important factors in the process of neointimal lesion formation after balloon injury. Moreover, they suggest that activation of FasL may decrease neointimal thickening after percutaneous coronary intervention.