The effect of omega-3 fatty acids on coronary atherosclerosis quantified by coronary computed tomography angiography.

Background & Aims: Data on the effects omega-3 fatty acids on coronary artery disease (CAD) are contradictory. While a recent metanalysis could not show improved cardiovascular outcomes, anti-atherogenic mechanisms are well known.

Objective: Aim was to assess the influence of Omega-3 polyunsaturated long-chain fatty acids (PUFA) supplementation on coronary atherosclerosis quantified by coronary computed tomography angiography (CTA).

Gene therapy with the angiogenic neuropeptide secretoneurin ameliorates experimental diabetic neuropathy.

The pathogenesis of diabetic neuropathy remains enigmatic. Damage to the vasa nervorum may be responsible for this disorder. Recently, we showed that secretoneurin (SN) induces angiogenesis in hindlimb and myocardial ischemia.

Evaluation of right ventricular function by coronary computed tomography angiography using a novel automated 3D right ventricle volume segmentation approach: a validation study.

Objectives: To evaluate right ventricle (RV) function by coronary computed tomography angiography (CTA) using a novel automated three-dimensional (3D) RV volume segmentation tool in comparison with clinical reference modalities.

Methods: Twenty-six patients with severe end-stage heart failure [left ventricle (LV) ejection fraction (EF) <35%] referred to CTA were enrolled. A specific individually tailored biphasic contrast agent injection protocol was designed (80%/20% high/low flow) was designed.

Nanoparticular delivery system for a secretoneurin derivative induces angiogenesis in a hind limb ischemia model.

Common therapeutic strategies for peripheral arterial disease often fail to re-establish sufficient blood flow within legs and feet of patients for avoiding critical limb ischemia, what is characterized by a substantial risk for amputation. The neuropeptide secretoneurin induces angiogenesis in models of limb and myocardial ischemia and might be a promising tool in the treatment of patients without the option of revascularization therapy for severe ischemia. Within this manuscript, the biologically active part of secretoneurin was identified, modified by induction of a cysteine residue to gain higher stability against enzymatic degradation and further packed into S-protected thiolated chitosan nanoparticles, which enable intra-muscular application of secretoneurin.

Secretoneurin gene therapy improves hind limb and cardiac ischaemia in Apo E⁻/⁻ mice without influencing systemic atherosclerosis.

Aims: Hypercholesterolaemia is a major risk factor for cardiovascular diseases and has been shown to influence angiogenesis in the hind limb ischaemia (HLI) model. The impaired up-regulation of angiogenic factors seems to be one of the underlying mechanisms for reduced vessel formation. Since we found that secretoneurin (SN) is up-regulated in hypoxic skeletal muscle cells and exerts beneficial effects in myocardial and HLI, we hypothesized that SN therapy might improve neovascularization in hypercholesterolaemic Apo E(-/-) (Apo E knockout) mice suffering from an impaired vascular response.

Secretoneurin gene therapy improves blood flow in an ischemia model in type 1 diabetic mice by enhancing therapeutic neovascularization.

Deficient angiogenesis after ischemia may contribute to worse outcome of peripheral arterial disease in patients with diabetes mellitus. Based on our previous work where we demonstrated that Secretoneurin (SN) is up-regulated under hypoxic conditions and enhances angiogenesis, we analyzed the therapeutic potential of SN gene therapy using a model of severe hind limb ischemia in streptozotocin-induced diabetic mice (STZ-DM). After induction of hind limb ischemia, blood flow was assessed by means of laser Doppler perfusion imaging (LDPI) and increased blood perfusion in the SN-treated animal group was observed.

Topical secretoneurin gene therapy accelerates diabetic wound healing by interaction between heparan-sulfate proteoglycans and basic FGF.

Diabetic foot ulcers represent a therapeutic problem of high clinical relevance. Reduced vascular supply, neuropathy and diminished expression of growth factors strongly contribute to wound healing impairment in diabetes. Secretoneurin, an angiogenic neuropeptide, has been shown to improve tissue perfusion in different animal models by increasing the amount of vessels in affected areas.

The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells.

Background: Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated by hypoxia, and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells.

Methods And Results: In vivo secretoneurin improved left ventricular function, inhibited remodeling, and reduced scar formation.

The neuropeptide catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism.

Rationale: The neuropeptide catestatin is an endogenous nicotinic cholinergic antagonist that acts as a pleiotropic hormone.

Objective: Catestatin shares several functions with angiogenic factors. We therefore reasoned that catestatin induces growth of new blood vessels.

The liver-selective thyromimetic T-0681 influences reverse cholesterol transport and atherosclerosis development in mice.

Background: Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLr, SR-BI, and apoE, as well as CETP transgenic mice.

Methodology/principal Findings: T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma cholesterol.

Influence of aspirin on SR-BI expression in human carotid plaques.

Background: We recently showed that aspirin promotes scavenger receptor class-B type I (SR-BI) protein expression in vitro in primary human macrophages and in vivo in resident peritoneal macrophages of mice.

Methods: We compared SR-BI and CD68 expression in carotid atherosclerotic specimens from endarterectomized patients with (n=38) or without (n=19) low-dose aspirin medication (100 mg/day) prior to endarterectomy.

Results: We found no differences concerning expression of CD68, indicating that aspirin did not influence macrophage content within atherosclerotic plaques.

The thyromimetic T-0681 protects from atherosclerosis.

This report describes studies in hyperlipidemic New Zealand White (NZW) rabbits investigating the impact of the liver-selective thyromimetic T-0681 on lipoprotein metabolism and the development of atherosclerosis. Prolonged treatment with T-0681 increased the hepatic expression of both LDL receptor and scavenger receptor class B, type I without affecting cholesteryl ester transfer protein activity. Upregulation of hepatic lipoprotein receptors was accompanied by a marked decrease of apolipoprotein B-containing lipoproteins, reflected by a 60% reduction of plasma cholesterol and a >70% reduction of plasma triglyceride levels.

Monocyte migration: a novel effect and signaling pathways of catestatin.

Several members of the neuropeptide family exert chemotactic actions on blood monocytes consistent with neurogenic inflammation. Furthermore, chromogranin A (CgA) containing Alzheimer plaques are characterized by extensive microglia activation and such activation induces neuronal damage. We therefore hypothesized that the catecholamine release inhibitory peptide catestatin (hCgA(352-372)) would induce directed monocyte migration.

The K121Q polymorphism of ENPP1 and peripheral arterial disease.

The K121Q variant of the ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1) gene is associated with obesity, insulin resistance, and early myocardial infarction. Therefore, we hypothesized that the K121Q polymorphism might also be associated with an increased risk for peripheral arterial disease. Four hundred patients with peripheral arterial disease and 400 controls matched for sex and age (+/- 2 years) were genotyped cross-sectionally for the K121Q single nucleotide polymorphism of the ENPP1 gene.

Reduced plasma high-density lipoprotein cholesterol in hyperthyroid mice coincides with decreased hepatic adenosine 5'-triphosphate-binding cassette transporter 1 expression.

The aim of the study was to investigate the influence of severe hyperthyroidism on plasma high-density lipoprotein cholesterol (HDL-C). Recently, it was shown in mice that increasing doses of T(3) up-regulate hepatic expression of scavenger receptor class B, type I, resulting in increased clearance of plasma HDL-C. Here, we show that severe hyperthyroidism in mice did not affect hepatic expression of scavenger receptor class B, type I, but reduced hepatic expression of ATP-binding cassette transporter 1, accompanied by a 40% reduction of HDL-C.

The MTP -493TT genotype is associated with peripheral arterial disease: results from the Linz Peripheral Arterial Disease (LIPAD) Study.

Objectives: Microsomal triglyceride transfer protein (MTP) transfers lipids into apoprotein B-containing lipoproteins for secretion from liver, intestine, and heart. We hypothesized the -493T single nucleotide polymorphism in the MTP promoter region to be associated with altered lipoprotein levels and with presence of peripheral arterial disease (PAD).

Design And Methods: 433 patients with symptomatic PAD and 433 controls matched for sex and age from the Linz Peripheral Arterial Disease (LIPAD) study were genotyped cross-sectionally for the -493T single nucleotide polymorphism in the promoter region of the MTP gene.

Scavenger receptor class B type I polymorphisms and peripheral arterial disease.

Genetic variations of the scavenger receptor class B type I (SR-BI) have been demonstrated to be associated with plasma lipid parameters, anthropomorphic parameters, and coronary artery disease. We determined the frequency of 3 single-nucleotide polymorphisms within the SR-BI gene (SCARB1) in 354 patients with peripheral arterial disease (PAD) and 354 controls matched for age, sex, and diabetes and related to lipids and disease state, that is, PAD. SCARB1 combined genotype exon 1/intron 5/exon 8 were found to be associated with plasma total and low-density lipoprotein cholesterol levels, respectively.

Low phospholipid transfer protein (PLTP) is a risk factor for peripheral atherosclerosis.

Objective: Phospholipid transfer protein (PLTP) facilitates cholesterol efflux from cells, intravascular HDL remodelling and transfer of vitamin E and endotoxin. In humans, the relationship of PLTP to atherosclerosis is unknown. However, strong coronary risk factors like obesity, diabetes, cigarette smoking and inflammation increase circulating levels of active PLTP.

Hypoxia up-regulates the angiogenic cytokine secretoneurin via an HIF-1alpha- and basic FGF-dependent pathway in muscle cells.

Expression of angiogenic cytokines like vascular endothelial growth factor is enhanced by hypoxia. We tested the hypothesis that decreased oxygen levels up-regulate the angiogenic factor secretoneurin. In vivo, muscle cells of mouse ischemic hind limbs showed increased secretoneurin expression, and inhibition of secretoneurin by a neutralizing antibody impaired the angiogenic response in this ischemia model.

Phospholipid transfer protein augments apoptosis in THP-1-derived macrophages induced by lipolyzed hypertriglyceridemic plasma.

Objective: Lipolysis of triglyceride-rich lipoproteins (TGRLPs) generates phospholipid-rich surface remnants and induces cytotoxic effects in adjacent vascular cells. We hypothesized that by integrating surface remnants into HDL, phospholipid transfer protein (PLTP) alleviates cytotoxicity.

Methods And Results: To test this hypothesis and gain insight into cytotoxicity during the postprandial phase in vivo, we injected normo-TG and hyper-TG human volunteers after a standardized fat meal (postprandial sample) with heparin, thereby stimulating lipolysis (postprandial heparinized sample).

Hepatic ENPP1 expression is induced in diabetic rabbits.

The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an inhibitor of the insulin receptor. Variants of ENPP1 are associated with infantile arterial calcification, obesity, and insulin resistance. To study the functional relevance of this protein in vivo, we cloned rabbit ENPP1 and studied its regulation in experimentally induced diabetes mellitus.

Aspirin regulates expression and function of scavenger receptor-BI in macrophages: studies in primary human macrophages and in mice.

Scavenger receptor class B type I (SR-BI) has been shown to be expressed in human atherosclerotic plaque macrophages, where it is believed to reduce atherosclerosis by promoting cholesterol efflux. In this study we investigated the influence of aspirin and other NSAIDs on SR-BI expression and function in cultured human macrophages as well as in different mouse strains. Incubation of human macrophages with 0.

Increased plasma levels of LDL cholesterol in rabbits after adenoviral overexpression of human scavenger receptor class B type I.

Scavenger receptor class B type I (SR-BI), a CD36 family member, plays a key role in high-density lipoprotein (HDL) metabolism, reverse cholesterol transport, and whole body cholesterol homeostasis, and is shown to be involved in the development of atherosclerosis in mice. In this report, we describe the effects of the adenoviral overexpression of human SR-BI (hSR-BI) in New Zealand White (NZW) rabbits, a wild-type animal model that expresses cholesteryl ester transfer protein (CETP) in plasma, displays a manlike lipoprotein profile, and is susceptible to atherosclerosis. A total of 1x10(12) adenoviral particles containing either hSR-BI or lacZ complementary deoxyribonucleic acid (control) were infused into the ear vein of NZW rabbits.

Phage-displayed recombinant single-chain antibody fragments with high affinity for cholesteryl ester transfer protein (CETP): cDNA cloning, characterization and CETP quantification.

Cholesteryl ester transfer protein (CETP) greatly affects the metabolism of all lipoprotein classes including low-density lipoprotein (LDL) and high-density lipoprotein (HDL), both known to constitute powerful risk factors for coronary artery disease (CAD). We now report the successful first cloning and characterization of single-chain antibody fragments specific for CETP. A recombinant phage display library was generated using spleen mRNA isolated from BALB/c mice that had been immunized with highly purified CETP.