Where hypertension happens.

Essential hypertension, which accounts for 90%-95% of all cases of hypertension seen in the clinic, is also referred to as idiopathic hypertension, because we simply don't understand the cause(s). Although many theories have been advanced, in the current issue of the JCI, Gonzalez-Villalobos et al. present further evidence implicating the intrarenal renin-angiotensin system and take us one step further by proposing a mechanism underlying this pathology.

Macrophage fusion is controlled by the cytoplasmic protein tyrosine phosphatase PTP-PEST/PTPN12.

Macrophages can undergo cell-cell fusion, leading to the formation of multinucleated giant cells and osteoclasts. This process is believed to promote the proteolytic activity of macrophages toward pathogens, foreign bodies, and extracellular matrices. Here, we examined the role of PTP-PEST (PTPN12), a cytoplasmic protein tyrosine phosphatase, in macrophage fusion.

Inpp4b is a novel negative modulator of osteoclast differentiation and a prognostic locus for human osteoporosis.

Inositol polyphosphate 4-phosphatase type II (Inpp4b) is a novel negative modulator of osteoclast differentiation and a prognostic locus for human osteoporosis. This short overview summarizes some of the cellular, molecular, and crosstalk signaling mechanisms that control osteoclast and osteoblast differentiation and activation.

Normal development and function but impaired memory phenotype of CD8⁺ T cells in transgenic mice expressing HIV-1 Nef in its natural target cells.

We studied the impact of HIV Nef on CD8(+) T cells in a mouse model of AIDS, the CD4C/HIV(Nef) transgenic (Tg) mice. We found that negative and positive thymic selections of CD8(+) T cells proceeded normally in Nef Tg mice bred respectively with HY or OT-1 TCR Tg mice. Tg peripheral CD8(+) T cells showed an activated phenotype and enhanced cell division in vivo and proliferated efficiently when stimulated in vitro with antigenic peptide.

Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin.

Unlabelled: The first seven members of the proprotein convertase (PC) family activate protein precursors by cleavage after basic residues. While PC7 has no known specific substrates, it shows redundancy with other PCs. A genome-wide association study suggested that circulating levels of shed human transferrin receptor 1 (hTfR1) are regulated by PC7.

The cytosolic adaptor AP-1A is essential for the trafficking and function of Niemann-Pick type C proteins.

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by over-accumulation of low-density lipoprotein-derived cholesterol and glycosphingolipids in late endosomes/lysosomes (LE/L) throughout the body. Human mutations in either NPC1 or NPC2 genes have been directly associated with impaired cholesterol efflux from LE/L. Independent from its role in cholesterol homeostasis and its NPC2 partner, NPC1 was unexpectedly identified as a critical player controlling intracellular entry of filoviruses such as Ebola.

Critical role of SAP in progression and reactivation but not maintenance of T cell-dependent humoral immunity.

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is a small adaptor molecule mutated in X-linked lymphoproliferative disease, a human immunodeficiency. SAP plays a critical role in the initiation of T cell-dependent B cell responses leading to germinal center reaction, the production of high-affinity antibodies, and B cell memory. However, whether SAP has a role in these responses beyond their initiation is not known.

Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies.

The discovery of PCSK9 in 2003 and its identification as the third protagonist responsible for ADH opened many new avenues of research in the cardiovascular field. Liver PCSK9 binds the LDLR and promotes its degradation in the endosomal/lysosomal pathway. A higher activity of PCSK9 leads to lower liver LDLR levels, resulting in a reduction in LDL-uptake from circulation, and thus in hypercholesterolemia and associated atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver.

High circulating cholesterol is associated with hypercholesterolemia, atherosclerosis, and stroke. However, the relation between cholesterol and tumorigenesis/metastasis is controversial. The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein cholesterol homeostasis by targeting the low-density lipoprotein receptor (LDLR) for degradation.

Potential implications of nanoparticle characterization on in vitro and in vivo gene delivery.

Nanoparticles are rapidly emerging as therapeutic delivery vectors defined by size-dependent properties. They offer several advantages over the traditional drug-delivery systems and medical diagnostics but also pose considerable challenges for systemic applications. Gene delivery is one of the important applications of nanotechnology.

Mouse model of intraluminal MCAO: cerebral infarct evaluation by cresyl violet staining.

Stroke is the third cause of mortality and the leading cause of disability in the World. Ischemic stroke accounts for approximately 80% of all strokes. However, the thrombolytic tissue plasminogen activator (tPA) is the only treatment of acute ischemic stroke that exists.

The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway.

PCSK9 enhances the cellular degradation of the LDL receptor (LDLR), leading to increased plasma LDL cholesterol. This multidomain protein contains a prosegment, a catalytic domain, a hinge region, and a cysteine-histidine rich domain (CHRD) composed of three tightly packed modules named M1, M2, and M3. The CHRD is required for the activity of PCSK9, but the mechanism behind this remains obscure.

The phosphatase PTP-PEST/PTPN12 regulates endothelial cell migration and adhesion, but not permeability, and controls vascular development and embryonic viability.

Protein-tyrosine phosphatase (PTP)-PEST (PTPN12) is ubiquitously expressed. It is essential for normal embryonic development and embryonic viability in mice. Herein we addressed the involvement of PTP-PEST in endothelial cell functions using a combination of genetic and biochemical approaches.

Notch-1 signaling promotes the cyclinD1-dependent generation of mammary tumor-initiating cells that can revert to bi-potential progenitors from which they arise.

In a previous work, we reported that young transgenic (Tg) mice expressing the intracellular domain of Notch1 (N1(IC)) showed expansion of lin(-) CD24(+) CD29(high) mammary cells enriched for stem cells and later developed mammary tumors. Mammary tumor formation was abolished or greatly reduced in cyclin D1(-/-) or cyclin D1(+/-) N1(IC) Tg mice, respectively. Here, we studied the epithelial cell subsets present in N1(IC)-induced tumors.

Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation.

Proprotein convertase subtilisin/kexin-9 (PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR). Deletion of PCSK9, and loss-of-function mutants in humans result in lower levels of circulating LDL-cholesterol and a strong protection against coronary heart disease. Accordingly, the quest for PCSK9 inhibitors has major clinical implications.

Loss of endothelial furin leads to cardiac malformation and early postnatal death.

In mammals, seven proprotein convertases (PCs) cleave secretory proteins after basic residues, and four of them are called furin-like PCs: furin, PC5, PACE4, and PC7. In vitro, they share many substrates. However, furin is essential during development since deficient embryos die at embryonic day 11 and exhibit multiple developmental defects, particularly defects related to the function of endothelial cells.

The adaptor SAP controls NK cell activation by regulating the enzymes Vav-1 and SHIP-1 and by enhancing conjugates with target cells.

The adaptor SAP, mutated in X-linked lymphoproliferative disease, has critical roles in multiple immune cell types. Among these, SAP is essential for the ability of natural killer (NK) cells to eliminate abnormal hematopoietic cells. Herein, we elucidated the molecular and cellular bases of this activity.

The biology and therapeutic targeting of the proprotein convertases.

The mammalian proprotein convertases constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. Seven of these (proprotein convertase 1 (PC1), PC2, furin, PC4, PC5, paired basic amino acid cleaving enzyme 4 (PACE4) and PC7) activate cellular and pathogenic precursor proteins by cleavage at single or paired basic residues, whereas subtilisin kexin isozyme 1 (SKI-1) and proprotein convertase subtilisin kexin 9 (PCSK9) regulate cholesterol and/or lipid homeostasis via cleavage at non-basic residues or through induced degradation of receptors. Proprotein convertases are now considered to be attractive targets for the development of powerful novel therapeutics.

Recent patents in siRNA delivery employing nanoparticles as delivery vectors.

Small interfering RNAs (siRNAs) are rapidly emerging as new therapeutic tools for the treatment of some of the deadly diseases such as cancer. However, poor cellular uptake and instability in physiological milieu limit its therapeutic potential, hence there arises a need of a delivery system which can efficiently and repeatedly deliver siRNA to the target cells. Nanoparticles have shown immense potential as suitable delivery vectors with enhanced efficacy and biocompatibility.

Protein tyrosine phosphatases in lymphocyte activation and autoimmunity.

Lymphocyte activation must be tightly regulated to ensure sufficient immunity to pathogens and prevent autoimmunity. Protein tyrosine phosphatases (PTPs) serve critical roles in this regulation by controlling the functions of key receptors and intracellular signaling molecules in lymphocytes. In some cases, PTPs inhibit lymphocyte activation, whereas in others they promote it.

Polyethylenimine as a promising vector for targeted siRNA delivery.

Recent discovery of RNA interference (RNAi) technology for gene therapy has triggered explosive research efforts towards development of small interfering RNA (siRNA) as therapeutic modality for gene silencing. Owing to its large molecular weight (~13 kDa), polyanionic nature (~40 negative phosphate groups) and rapid enzymatic degradation, delivery of siRNA remains an unresolved issue. Hence, there arises a need of an appropriate delivery vector to overcome the intrinsic, poor intracellular uptake and limited in vitro and in vivo stability.

Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice.

Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes independently of its enzymatic activity the degradation of the low-density lipoprotein (LDL) receptor. PCSK9 gain of function in humans leads to autosomal dominant hypercholesterolemia, whereas the absence of functional PCSK9 results in ≈7-fold lower levels of LDL cholesterol. This suggests that lowering PCSK9 may protect against atherosclerosis.

The CD4C/HIV(Nef)transgenic model of AIDS.

CD4C/HIVNef Tg mice express HIV-1 Nef in relevant target cells through the regulatory sequences of the human CD4 gene. These mice develop a severe disease showing many characteristics of human AIDS. A summary of the results obtained with these Tg mice is presented.