Antihypertensive treatment with hydrochlorothiazide-hydralazine combination aggravates medial vascular calcification in CKD rats with mineral bone disorder.

Background: Arterial stiffness and medial vascular calcification, leading to isolated systolic blood pressure (BP), are major cardiovascular risk factors in patients with chronic kidney disease (CKD) and mineral bone disorders (MBD). The impact of BP on MBD-induced medial vascular calcification in CKD remains uncertain. We investigated whether BP reduction improves arterial stiffness and medial vascular calcification in a rat model of CKD-MBD.

The adenoviral protein E4orf4: a probing tool to decipher mechanical stress-induced nuclear envelope remodeling in tumor cells.

The human adenovirus (Ad) type 2/5 early region 4 (E4) ORF4 protein (E4orf4) exerts a remarkable tumor cell-selective killing activity in mammalian cells. This indicates that E4orf4 can target tumor cell-defining features and is a unique tool to probe cancer cell vulnerabilities. Recently, we found that E4orf4, through an interaction with the polarity protein PAR3, subverts nuclear envelope (NE) remodeling processes in a tumor cell-selective manner.

Adenoviral protein E4orf4 interacts with the polarity protein Par3 to induce nuclear rupture and tumor cell death.

The tumor cell-selective killing activity of the adenovirus type 2 early region 4 ORF4 (E4orf4) protein is poorly defined at the molecular level. Here, we show that the tumoricidal effect of E4orf4 is typified by changes in nuclear dynamics that depend on its interaction with the polarity protein Par3 and actomyosin contractility. Mechanistically, E4orf4 induced a high incidence of nuclear bleb formation and repetitive nuclear ruptures, which promoted nuclear efflux of E4orf4 and loss of nuclear integrity.

Selective HIF-1 Regulation under Nonhypoxic Conditions by the p42/p44 MAP Kinase Inhibitor PD184161.

Hypoxia-inducible factor-1 (HIF-1) is a key gene regulator for cellular adaptation to low oxygen. In addition to hypoxia, several nonhypoxic stimuli, including hormones and growth factors, are essential for cell-specific HIF-1 regulation. Our studies have highlighted angiotensin II (AngII), a vasoactive hormone, as a potent HIF-1 activator in vascular smooth muscle cells (VSMC).

Endothelin type A receptor blockade reduces vascular calcification and inflammation in rats with chronic kidney disease.

Objective: Arterial stiffness and calcification are nontraditional cardiovascular risk factors in chronic kidney disease (CKD). Using a rat model of CKD with mineral imbalance, medial vascular calcification has been associated with inflammation and increased endothelin-1 (ET-1) production. We therefore hypothesized that ET-1, through the endothelin type A (ETA) receptor, induces vascular inflammation, calcification and stiffness in CKD.

Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification.

Medial vascular calcification is a common complication of chronic kidney disease (CKD). Although elevated inorganic phosphate stimulates vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and calcification, the mechanisms involved in their calcification during CKD are not fully defined. Because hypoxic gene activation is linked to CKD and stimulates bone cell osteogenic differentiation, we used in vivo and in vitro rodent models to define the role of hypoxic signaling during elevated inorganic phosphate-induced VSMC calcification.

Inflammatory cytokines and reactive oxygen species as mediators of chronic kidney disease-related vascular calcification.

Background: Vascular calcification, a regulated process in chronic kidney disease (CKD), requires vascular smooth muscle cell (VSMC) differentiation into osteoblast-like cells. This phenomenon can be enhanced by inflammatory cytokines and production of reactive oxygen species (ROS). In CKD rats with vascular calcification, we investigated whether inflammatory cytokines, ROS generation, and downstream signaling events are associated with CKD-related vascular calcification.

The prolyl isomerase Pin1 regulates hypoxia-inducible transcription factor (HIF) activity.

Hypoxia-inducible transcription factor-1 (HIF-1) plays a decisive role in cell survival and adaptation to hypoxic stress by controlling the expression of genes involved in oxygen homeostasis. HIF-1 activity is fine-tuned through specific post-translational modifications of its essential HIF-1α subunit. Among these modifications, phosphorylation is important for HIF-1 transcriptional activity.

Transcriptional repression of hypoxia-inducible factor-1 (HIF-1) by the protein arginine methyltransferase PRMT1.

Hypoxia-inducible factors (HIF-1 and HIF-2) are essential mediators for the adaptive transcriptional response of cells and tissues to low-oxygen conditions. Under hypoxia or when cells are treated with various nonhypoxic stimuli, the active HIF-α subunits are mainly regulated through increased protein stabilization. For HIF-1α, it is clear that further transcriptional, translational, and posttranslational regulations are important for complete HIF-1 activity.

The Werner syndrome gene product (WRN): a repressor of hypoxia-inducible factor-1 activity.

Werner syndrome (WS) is a rare autosomal disease characterized by the premature onset of several age-associated pathologies. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA repair, replication, transcription and telomere maintenance. Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of genes essential for adaptation to low oxygen conditions.

Conserved molecular interactions within the HBO1 acetyltransferase complexes regulate cell proliferation.

Acetyltransferase complexes of the MYST family with distinct substrate specificities and functions maintain a conserved association with different ING tumor suppressor proteins. ING complexes containing the HBO1 acetylase are a major source of histone H3 and H4 acetylation in vivo and play critical roles in gene regulation and DNA replication. Here, our molecular dissection of HBO1/ING complexes unravels the protein domains required for their assembly and function.

Tumor necrosis factor inhibitors as novel therapeutic tools for vascular remodeling diseases.

Vascular remodeling diseases (VRDs) are characterized by enhanced inflammation and proliferative and apoptosis-resistant vascular smooth muscle cells (VSMCs). The sustainability of this phenotype has been attributed in part to the activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). There is evidence that circulating cytokines can act as HIF-1 activators in a variety of tissues, including VSMCs.

Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen species.

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for responses to low oxygen. Different nonhypoxic stimuli, including hormones and growth factors, are also important HIF-1 activators in the vasculature. Angiotensin II (Ang II), the main effecter hormone in the renin-angiotensin system, is a potent HIF-1 activator in vascular smooth muscle cells (VSMCs).

HIF-1 inhibition decreases systemic vascular remodelling diseases by promoting apoptosis through a hexokinase 2-dependent mechanism.

Aims: Vascular remodelling diseases are characterized by the presence of proliferative and apoptosis-resistant vascular smooth muscle cells (VSMC). There is evidence that pro-proliferative and anti-apoptotic states are characterized by metabolic remodelling (a glycolytic phenotype with hyperpolarized mitochondria) involving Akt pathway activation by circulating growth factors. Hypoxia-inducible factor-1 (HIF-1) is involved in different vascular diseases.

Effects of TGF-beta1 on endothelial factors.

This study investigated the mechanistic effect of transforming growth factor-beta1 (TGFbeta1) on the endothelial mediators: endothelin-1 (ET-1), prostacyclin (PGI(2)) and nitric oxide (NO) in the endothelial cell line 1G11. Endothelial cells were incubated with increasing concentrations of TGFbeta1 in the presence and absence of growth medium (deprived) or various inhibitors. In deprived cells, TGFbeta1 increased the release of PGI(2) (6-keto-PGF1alpha) concomitantly to an increase in COX-2 expression, whereas the production of ET-1 and NO metabolites was not affected.

Sphingosine-1-phosphate: a novel nonhypoxic activator of hypoxia-inducible factor-1 in vascular cells.

Objective: Sphingosine-1-phosphate (S1P) is a potent bioactive phospholipid responsible for a variety of vascular cell responses. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of genes essential for adaptation to low oxygen. S1P and HIF-1 are both important mediators of vascular cell responses such as migation, proliferation, and survival.

TGFbeta-induced GRK2 expression attenuates AngII-regulated vascular smooth muscle cell proliferation and migration.

Through diametric actions, the transforming growth factor beta (TGFbeta) and Angiotensin II (AngII) play important roles in regulating various biological responses such as cell proliferation and migration. Signaling initiated by TGFbeta and AngII occurs through two structurally and functionally distinct receptor super families,the serine/threonine kinase and G protein-coupled receptors (GPCRs). Previously, we identified the Gprotein-coupled receptor kinase-2 (GRK2), a key regulatory factor in the desensitization of GPCRs, as a direct downstream target of the TGFbeta signaling cascade.

(2R)-[(4-Biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a matrix metalloprotease inhibitor, is a novel and potent activator of hypoxia-inducible factors.

Hypoxia-inducible factors (HIFs) are unstable heterodimeric transcription factors and decisive elements for the transcriptional regulation of genes important in the adaptation to low-oxygen conditions. Hypoxia is the ubiquitous inducer of HIFs, stabilizing the alpha-subunit and permitting the formation of a functional HIF complex. Here, we identify (2R)-[(4-biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a commercially available metalloprotease-2 and -9 inhibitor, as a rapid and potent inducer of HIFs.

Hypoxia-inducible factor-1alpha stabilization in nonhypoxic conditions: role of oxidation and intracellular ascorbate depletion.

Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of many genes induced under low oxygen conditions. Under normal oxygen conditions, HIF-1alpha, the active subunit of HIF-1, is hydroxylated on proline residues by specific HIF prolyl-hydroxylases, leading to ubiquitination and degradation by the proteasome. In hypoxia, hydroxylation and ubiquitination are blocked and HIF-1alpha accumulates in cells.

Differential regulation of hypoxia-inducible factor-1 through receptor tyrosine kinase transactivation in vascular smooth muscle cells.

Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of many genes expressed in hypoxic conditions. In vascular smooth muscle cells, the vasoactive hormone angiotensin II (Ang II) is a very potent inducer and activator of HIF-1. As opposed to hypoxia, which induces HIF-1alpha by protein stabilization, Ang II induced HIF-1alpha through transcriptional and translational mechanisms.

Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression.

The hypoxia-inducible transcription factor-1 (HIF-1) is central to a number of pathological processes through the induction of specific genes such as vascular endothelial growth factor (VEGF). Even though HIF-1 is highly regulated by cellular oxygen levels, other elements of the inflammatory and tumor microenvironment were shown to influence its activity under normal oxygen concentration. Among others, recent studies indicated that transforming growth factor (TGF) beta increases the expression of the regulatory HIF-1alpha subunit, and induces HIF-1 DNA binding activity.

[HIF-1 activation during tumor progression: implications and consequences].

The transcription factor hypoxia-inducible factor 1 (HIF-1) regulates the expression of more than 70 genes in response to hypoxic stress. Composed of two subunits, HIF-1 activity is modulated by the availability of the HIF-1alpha protein subunit. The stability and transcriptional activity of this extremely labile protein is affected by post-translational modifications.

Arrest-defective-1 protein, an acetyltransferase, does not alter stability of hypoxia-inducible factor (HIF)-1alpha and is not induced by hypoxia or HIF.

The hypoxia-inducible factor (HIF) is a key player in a transcriptional pathway that controls the hypoxic response of mammalian cells. Post-translational modification of the alpha subunit of HIF determines its half-life and activity. Among the multiple reported modifications, acetylation, by an acetyltransferase termed arrest-defective-1 protein (ARD1), has been reported to decrease HIF-1alpha stability and therefore impact on hypoxic gene expression.

Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators.

Oxygen availability is crucial for cellular metabolism. Hypoxia-inducible factor 1 (HIF-1) is the major oxygen homeostasis regulator. Under normoxic conditions, HIF-1 is rapidly degraded by the proteasome.