Alternatively spliced tissue factor promotes plaque angiogenesis through the activation of hypoxia-inducible factor-1α and vascular endothelial growth factor signaling.

Background: Alternatively spliced tissue factor (asTF) is a novel isoform of full-length tissue factor, which exhibits angiogenic activity. Although asTF has been detected in human plaques, it is unknown whether its expression in atherosclerosis causes increased neovascularization and an advanced plaque phenotype.

Methods And Results: Carotid (n=10) and coronary (n=8) specimens from patients with stable or unstable angina were classified as complicated or uncomplicated on the basis of plaque morphology.

An increase of VEGF plasma levels is associated with restenosis of drug-eluting stents.

Aims: Drug-eluting stents (DES) reduce late lumen loss compared to bare metal stents but were not able to eradicate in-stent restenosis (ISR) fully. Vascular endothelial growth factor (VEGF) may inhibit late lumen loss through accelerated reendothelialisation, but may also promote neointima formation by proinflammatory effects. The aim of this study was to evaluate whether endogenous plasma levels of VEGF are associated with development of ISR after implantation of DES.

Novel small leucine-rich repeat protein podocan is a negative regulator of migration and proliferation of smooth muscle cells, modulates neointima formation, and is expressed in human atheroma.

Background: Smooth muscle cell (SMC) migration and proliferation critically influence the clinical course of vascular disease. We tested the effect of the novel small leucine-rich repeat protein podocan on SMC migration and proliferation using a podocan-deficient mouse in combination with a model of arterial injury and aortic explant SMC culture. In addition, we examined the effect of overexpression of the human form of podocan on human SMCs and tested for podocan expression in human atherosclerosis.

Macrophages transmit potent proangiogenic effects of oxLDL in vitro and in vivo involving HIF-1α activation: a novel aspect of angiogenesis in atherosclerosis.

Neovascularization has been linked to the progression and vulnerability of atherosclerotic lesions. Angiogenesis is increased in lipid-rich plaque. Hypoxia-inducible factor alpha (HIF-1α) is a key transcriptional regulator responding to hypoxia and activating genes, which promote angiogenesis, among them vascular endothelial growth factor (VEGF).

Accelerated reendothelialization, increased neovascularization and erythrocyte extravasation after arterial injury in BAMBI-/- mice.

Background: Intimal injury rapidly activates TGFβ and enhances vascular repair by the growth of endothelial (EC) and vascular smooth muscle cells (VSMC). The response to the TGFβ family of growth factors can be modified by BAMBI (BMP, Activin, Membrane Bound Inhibitor) acting as a non-signaling, competitive antagonist of TGFβ type I receptors such as ALK 1 and 5. In vivo the effect of BAMBI will depend on its cell-specific expression and of that of the ALK type receptors.

Inactivation of nuclear factor-Y inhibits vascular smooth muscle cell proliferation and neointima formation.

Objective: Atherosclerosis and restenosis are multifactorial diseases associated with abnormal vascular smooth muscle cell (VSMC) proliferation. Nuclear factor-Y (NF-Y) plays a major role in transcriptional activation of the CYCLIN B1 gene (CCNB1), a key positive regulator of cell proliferation and neointimal thickening. Here, we investigated the role of NF-Y in occlusive vascular disease.

Coronary artery disease in aging women: a menopause of endothelial progenitor cells?

The cardiovascular protection provided to women during the reproductive age and the unique angiogenic properties of the female reproductive system provide insights into the complex regulatory network of female sex hormones, angiogenic growth factors, and stem cell regulatory molecules. The intricate and interwoven endometrial physiology of the female menstrual cycle shows that in order to harness the physiologic cardioprotection provided by nature to women of reproductive age, for better cardiovascular therapies in postmenopausal women and the population in general, a coherent and systematic approach is needed.

Carvedilol administration in acute myocardial infarction results in stronger inhibition of early markers of left ventricular remodeling than metoprolol.

Background: The structural secuelae of acute myocardial infarction (AMI) is mostly dictated by left ventricular (LV) remodelling, leading to heart failure. Monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a critical role in LV remodelling. β-blockers are first line therapy for AMI and heart failure; however, the mechanisms responsible for their benefits remain poorly understood.

The complement component C5a is present in human coronary lesions in vivo and induces the expression of MMP-1 and MMP-9 in human macrophages in vitro.

The complement component C5a is formed during activation of the complement cascade and exerts chemotactic and proinflammatory effects. Macrophages, which are localized in the rupture-prone shoulder regions of coronary plaques, are thought to play a major role in plaque destabilization and rupture through the production of matrix metalloproteinases (MMPs). When human monocyte-derived macrophages were stimulated in vitro with C5a, MMP-1 and MMP-9 mRNA levels were significantly increased.

Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model.

Aims: Aortic stenosis (AS) is associated with significant morbidity and mortality. Recombinant apolipoprotein A-I Milano (rApoA-I(M)) induces atherosclerotic plaque regression. The aims of this study were to determine the effects of rApoA-I(M) on experimental aortic valve degeneration and its mechanisms of action.

The cardioprotection granted by metoprolol is restricted to its administration prior to coronary reperfusion.

Background: Myocardial infarct size is a strong predictor of cardiovascular events. Intravenous metoprolol before coronary reperfusion has been shown to reduce infarct size; however, it is unknown whether oral metoprolol initiated early after reperfusion, as clinical guidelines recommend, is similarly cardioprotective. We compared the extent of myocardial salvage associated with intravenous pre-reperfusion-metoprolol administration in comparison with oral post-reperfusion-metoprolol or placebo.

The electrical substrate of vagal atrial fibrillation as assessed by the signal-averaged electrocardiogram of the P wave.

Background: The autonomic nervous system is thought to be involved in the initiation of atrial fibrillation (AF). However, there is a distinct entity of vagal AF characterized by episodes occurring at rest, postprandially, or during sleep. The purpose of this study was to compare intraatrial conduction in patients with vagally mediated AF to those with nonvagal AF, using the signal-averaged electrocardiogram (SAECG) of P wave.

Reduced acute vascular injury and atherosclerosis in hyperlipidemic mice transgenic for lysozyme.

Hyperlipidemia promotes oxidant stress, inflammation, and atherogenesis in apolipoprotein E-deficient (ApoE((-/-))) mice. Mice transgenic for lysozyme (LZ-Tg) are resistant to acute and chronic oxidative stress and have decreased circulating levels of pro-oxidant advanced glycation end-products (AGEs). Herein we report that TIB-186 macrophages transduced with adenovirus-expressing human LZ (AdV-LZ) containing the AGE-binding domain facilitated AGE uptake and degradation and that AdV-LZ-transduced macrophages and peritoneal macrophages from LZ-Tg mice suppressed the AGE-triggered tumor necrosis factor-alpha response.

Fenofibrate induces plaque regression in hypercholesterolemic atherosclerotic rabbits: in vivo demonstration by high-resolution MRI.

Introduction: Fenofibrate has shown to reduce major cardiovascular events and slow angiographic progression of coronary atherosclerosis. The postulated mechanism of action is via the activation of peroxisomal proliferator-activated receptor-alpha (PPAR-alpha), a nuclear transcription factor that controls a variety of cellular functions. We investigated the anti-atherogenic effects of fenofibrate on previously established experimental atherosclerotic lesions.

Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition--a magnetic resonance imaging study.

Aims: Endothelial dysfunction, platelet hyperactivity, and inflammation play a crucial role in atherogenesis. A growing body of evidence suggests that inhibition of the thromboxane A2 (TxA2 or TP) receptor may improve endothelial function and reduce the inflammatory component of atherosclerosis in addition to its demonstrated antiplatelet activity. Consequently, we sought to assess the effect of a novel TP receptor antagonist S18886, on atherosclerotic lesion progression and composition by serial non-invasive magnetic resonance imaging (MRI).

Vascular endothelial growth factor regulates reendothelialization and neointima formation in a mouse model of arterial injury.

Background: The rate of reendothelialization is critical in neointima formation after arterial injury. Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, has been advocated for accelerating endothelial repair and preventing intimal hyperplasia after percutaneous coronary interventions. However, the precise mechanism of action of VEGF treatment and the physiologic role of endogenous VEGF after arterial injury are not well described.

Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis.

Recent developments into antherothrombosis, the leading cause of morbidity and mortality in Western Society, may help to change our treatment strategy to a more casual approach. The composition of the atherosclerotic plaque, rather than the percent stenosis, appears to be a critical predictor for both risk of plaque rupture and subsequent thrombogenicity. A large lipid core, rich in tissue factor (TF) and inflammatory cells including macrophages, and a thin fibrous cap with compromise of its structural integrity by matrix degrading enzymes, such as metalloproteinases (MMPs), render a lesion susceptible to rupture and subsequent acute thrombosis.

Caspase-3 and tissue factor expression in lipid-rich plaque macrophages: evidence for apoptosis as link between inflammation and atherothrombosis.

Background: Macrophages associated with arterial wall lipid deposition contribute to inflammatory processes. Tissue factor (TF) has been implicated in the thrombogenicity of atherosclerotic plaques. Intimal cells undergoing apoptosis have been postulated as a source for TF.

Dendritic cells in neointima formation after rat carotid balloon injury: coordinated expression withanti-apoptotic Bcl-2 and HSP47 in arterial repair.

Objectives: We sought to evaluate: 1) the contribution of dendritic cells (DCs); and 2) the impact of B-cell lymphoma 2 protein (Bcl-2), a central anti-apoptotic protooncogene, and of heat shock protein 47 (HSP47), indicating subsequent collagen deposition, in neointima formation after angioplasty.

Background: The origin of neointimal cells and the factors that promote their accumulation are still unclear. Previous studies reported intimal presence of DCs and suggested cells of primarily extravascular origin to contribute to arterial repair.

Decreased reendothelialization and increased neointima formation with endostatin overexpression in a mouse model of arterial injury.

Background: Impaired endothelial regeneration contributes to arterial lesion formation. Endostatin is a specific inhibitor of endothelial cell growth and induces endothelial cell apoptosis. We examined the effect of endostatin overexpression on reendothelialization and neointima formation in a mouse model of arterial injury.