Effect of Heme Oxygenase-1 on Matrix Metalloproteinase-3 Expression in Human Fibroblasts

Heme oxygenase-1(HO-1) is an enzyme that plays a very important role in the resolution of inflammation. HO-1-based therapies are effective in a number of disease conditions. However, HO-1 also increases tumor growth, angiogenesis, metastasis and chemoresistance. Matrix metalloproteinase-3 (MMP-3) is an enzyme involved in physiological and pathophysiological tissue remodeling. Unbalanced expression of MMPs is a key feature of connective tissue destruction in chronic inflammatory conditions. Previously shown in this laboratory, the HO-1 inducer, hemin, increased MMP-3 mRNA expression in some HGF cultures. To assess whether HO-1 and/or its products regulate expression of MMP-3 in human fibroblasts, the effect of HO-1 on MMP-3 mRNA expression was tested in HGF, HFF, and MG-63 cell lines. Cobalt protoporphyrin IX(CoPP) was used to induce HO-1 and Tin protoporphyrin IX(SnPP) was used to inhibit HO-1 activity. MMP-3 mRNA levels were quantified using real time PCR and normalized to GAPDH mRNA levels. Treatment of fibroblast cell cultures (HGF, HFF, MG-63) with CoPP did not result in significant changes in basal or IL-1-induced MMP-3 mRNA expression. Likewise, treatment with SnPP did not cause significant changes in MMP-3 expression. These results imply that HO-1 and its products are probably not responsible for most of the increase in MMP-3 expression seen in some HGF cell cultures in response to hemin

The effect of low-dose proteasome inhibition on pre-existing atherosclerosis in LDL receptor-deficient mice

Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in atherosclerosis development. However, the nature of UPS dysfunction has been proposed to be specific to certain stages of atherosclerosis development, which has implications for proteasome inhibition as a potential treatment option. Recently, low-dose proteasome inhibition with bortezomib has been shown to attenuate early atherosclerosis in low-density lipoprotein receptor-deficient (LDLR(-/-)) mice. The present study investigates the effect of low-dose proteasome inhibition with bortezomib on pre-existing advanced atherosclerosis in LDLR(-/-) mice. We found that bortezomib treatment of LDLR(-/-) mice with pre-existing atherosclerosis does not alter lesion burden. Additionally, macrophage infiltration of aortic root plaques, total plasma cholesterol levels, and pro-inflammatory serum markers were not influenced by bortezomib. However, plaques of bortezomib-treated mice exhibited larger necrotic core areas and a significant thinning of the fibrous cap, indicating a more unstable plaque phenotype. Taking recent studies on favorable effects of proteasome inhibition in early atherogenesis into consideration, our data support the hypothesis of stage-dependent effects of proteasome inhibition in atherosclerosis

PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells

Endothelial pro-inflammatory activation plays a pivotal role in atherosclerosis, and many pro-inflammatory and atherogenic signals converge upon mechanistic target of rapamycin (mTOR). Inhibitors of mTOR complex 1 (mTORC1) reduced atherosclerosis in preclinical studies, but side effects including insulin resistance and dyslipidemia limit their clinical use in this context. Therefore, we investigated PRAS40, a cell type-specific endogenous modulator of mTORC1, as alternative target. Indeed, we previously found PRAS40 gene therapy to improve metabolic profile; however, its function in endothelial cells and its role in atherosclerosis remain unknown. Here we show that PRAS40 negatively regulates endothelial mTORC1 and pro-inflammatory signaling. Knockdown of PRAS40 in endothelial cells promoted TNFα-induced mTORC1 signaling, proliferation, upregulation of inflammatory markers and monocyte recruitment. In contrast, PRAS40-overexpression blocked mTORC1 and all measures of pro-inflammatory signaling. These effects were mimicked by pharmacological mTORC1-inhibition with torin1. In an in vivo model of atherogenic remodeling, mice with induced endothelium-specific PRAS40 deficiency showed enhanced endothelial pro-inflammatory activation as well as increased neointimal hyperplasia and atherosclerotic lesion formation. These data indicate that PRAS40 suppresses atherosclerosis via inhibition of endothelial mTORC1-mediated pro-inflammatory signaling. In conjunction with its favourable effects on metabolic homeostasis, this renders PRAS40 a potential target for the treatment of atherosclerosis

Thermoelectric cross-plane properties on p- and n-Ge/SixGe1-x superlattices

Silicon and germanium materials have demonstrated an increasing attraction for energy harvesting, due to their sustainability and integrability with complementary metal oxide semiconductor and micro-electro-mechanical-system technology. The thermoelectric efficiencies for these materials, however, are very poor at room temperature and so it is necessary to engineer them in order to compete with telluride based materials, which have demonstrated at room temperature the highest performances in literature [1]. Micro-fabricated devices consisting of mesa structures with integrated heaters, thermometers and Ohmic contacts were used to extract the cross-plane values of the Seebeck coefficient and the thermal conductivity from p- and n-Ge/SixGe1-x superlattices. A second device consisting in a modified circular transfer line method structure was used to extract the electrical conductivity of the materials. A range of p-Ge/Si0.5Ge0.5 superlattices with different doping levels was investigated in detail to determine the role of the doping density in dictating the thermoelectric properties. A second set of n-Ge/Si0.3Ge0.7 superlattices was fabricated to study the impact that quantum well thickness might have on the two thermoelectric figures of merit, and also to demonstrate a further reduction of the thermal conductivity by scattering phonons at different wavelengths. This technique has demonstrated to lower the thermal conductivity by a 25% by adding different barrier thicknesses per period

Ultra-high critical current densities of superconducting YBa2_2Cu3_3O7−δ_{7-\delta} thin films in the overdoped state

Doping is one of the most relevant paths to tune the functionality of cuprates, it determines carrier density and the overall physical properties of these impressive superconducting materials. We present an oxygen doping study of YBa$_2$Cu$_3$O$_{7-\delta}$ (YBCO) thin films from underdoped to overdoped state, correlating the measured charge carrier density, $n_\textrm{H}$, the hole doping, $p$, and the critical current density, $J_\textrm{c}$. Our results show a continuous increase of $J_\textrm{c}$ with charge carrier density, reaching 90 MA/cm$^2$ at 5 K for $p$-doping at the Quantum Critical Point (QCP), linked to an increase of the superconducting condensation energy. The ultra-high $J_\textrm{c}$ achived corresponds to a third of the depairing current, i.e. a value 60 % higher than ever reported in YBCO films. The overdoped regime is characterized by a sudden increase of $n_\textrm{H}$, associated to the reconstruction of the Fermi-surface at the QCP. Overdoping YBCO opens a promising route to extend the current carrying capabilities of REBCO coated conductors for applications

Demonstration and characterization of α-human atrial natriuretic factor in human plasma

AbstractThis paper describes a highly specific and sensitive radioimmunoassay for α-human atrial natriuretic factor (α-hANF), the C-terminal 28-amino-acid residue portion of human prepro-ANF in human plasma. A novel extraction and prepurification procedure allowed for detection of levels of immunoreactive-α-hANF as low as 0.5 fmolml. In normotensive subjects, levels in the range 1–23 fmolml (mean = 8.9 fmolml) were found. Combined gel permeation and HPLC analysis demonstrated that this ir-α-hANF was comprised virtually exclusively of authentic 28-residue β-hANF. No evidence for occurrence of larger precursor forms in human plasma was acquired. A heterogenous group of hypertensive patients displayed considerably higher levels (mean = 62.2 fmolml), of interest in view of the hypotensive properties of ANF.Atrial natriuretic factorHuman plasmaExtractionChromatographie characterizationHypertensio

Role of Kozak sequence polymorphism of platelet glycoprotein Ibα as a risk factor for coronary artery disease and catheter interventions

AbstractOBJECTIVESWe sought to determine the role of the −5T/C polymorphism of the platelet glycoprotein (GP) Ibα as a potential risk factor for coronary artery disease (CAD) and adverse events complicating a coronary catheter intervention.BACKGROUNDThe platelet GP Ib-IX-V receptor complex plays a crucial role in arterial thrombus formation. The −5T/C polymorphism of GP Ibα is associated with increased receptor density.METHODSWe genotyped 1,000 patients with angiographically confirmed CAD, as well as 1,000 age- and gender-matched control subjects, for this polymorphism by polymerase chain reaction/restriction fragment length polymorphism. Among the patients with CAD, 269 underwent percutaneous transluminal coronary angioplasty (PTCA), 103 underwent directional coronary atherectomy and 278 underwent stenting. This intervention group was followed for a 30-day composite end point of target vessel revascularization, myocardial infarction or death.RESULTSCarriers of the −5C allele were significantly over-represented in the group of patients developing acute coronary syndromes (relative risk [RR] 1.43, 95% confidence interval [CI] 1.05 to 1.95, p = 0.02). The −5C allele furthermore predicted an increased risk for developing complications after PTCA (RR 3.75, 95% CI 1.15 to 12.27, p = 0.029).CONCLUSIONSThe −5C allele of the GP Ibα Kozak polymorphism may represent a risk factor in clinical conditions in which thrombosis plays an important role, such as in acute coronary syndromes and in complications after PTCA