The Protein Kinase A Inhibitor KT5720 Prevents Endothelial Dysfunctions Induced by High-Dose Irradiation.

High-dose irradiation can trigger numerous endothelial dysfunctions, including apoptosis, the overexpression of adhesion molecules, and alteration of adherens junctions. Altogether, these endothelial dysfunctions contribute to the development of tissue inflammation and organ damage. The development of endothelial dysfunctions may depend on protein phosphorylation by various protein kinases, but the possible role of protein kinase A (PKA) has not been investigated so far, and efficient compounds able to protect the endothelium from irradiation effects are needed.

Two-pore channels (TPCs) acts as a hub for excitation-contraction coupling, metabolism and cardiac hypertrophy signalling.

Ca signaling is essential for cardiac contractility and excitability in heart function and remodeling. Intriguingly, little is known about the role of a new family of ion channels, the endo-lysosomal non-selective cation "two-pore channel" (TPCs) in heart function. Here we have used double TPC knock-out mice for the 1 and 2 isoforms of TPCs (Tpcn1/2) and evaluated their cardiac function.

Niemann-Pick C1 protein regulates platelet membrane-associated calcium ion signaling in thrombo-occlusive diseases in mice.

Background: Pathophysiologic platelet activation leads to thrombo-occlusive diseases such as myocardial infarction or ischemic stroke. Niemann-Pick C1 protein (NPC1) is involved in the regulation of lysosomal lipid trafficking and calcium ion (Ca) signaling, and its genetic mutation causes a lysosomal storage disorder. Lipids and Ca are key players in the complex orchestration of platelet activation.

ADP receptor P2Y12 is the capstone of the cross-talk between Ca mobilization pathways dependent on Ca ATPases sarcoplasmic/endoplasmic reticulum type 3 and type 2b in platelets.

Background: Blood platelet Ca stores are regulated by 2 Ca-ATPases (SERCA2b and SERCA3). On thrombin stimulation, nicotinic acid adenosine dinucleotide phosphate mobilizes SERCA3-dependent stores, inducing early adenosine 5'-diphosphate (ADP) secretion, potentiating later SERCA2b-dependent secretion.

Objectives: The aim of this study was to identify which ADP P2 purinergic receptor (P2Y1 and/or P2Y12) is(are) involved in the amplification of platelet secretion dependent on the SERCA3-dependent Ca mobilization pathway (SERCA3 stores mobilization) as triggered by low concentration of thrombin.

The immunosuppressant drug Cyclosporin A aggravates irradiation effects in endothelial cells.

The immunosuppressant drug Cyclosporin A (CsA) has been widely used to prevent the development of Graft-versus-Host Disease (GvHD) that can occur after transplantation, including allogeneic graft after accidental high-dose irradiation in humans. Here, we show that CsA alone stimulates ICAM-1 overexpression in human pulmonary microvascular endothelial cells (HPMECs) through Toll-Like Receptor 4 (TLR4) and NF-κB activation. In HPMECs, CsA treatment significantly worsened the overexpression of ICAM-1 induced by high-dose irradiation (15 Gy).

Endoglin Is an Endothelial Housekeeper against Inflammation: Insight in ECFC-Related Permeability through LIMK/Cofilin Pathway.

Endoglin (Eng) is an endothelial cell (EC) transmembrane glycoprotein involved in adhesion and angiogenesis. Eng mutations result in vessel abnormalities as observed in hereditary hemorrhagic telangiectasia of type 1. The role of Eng was investigated in endothelial functions and permeability under inflammatory conditions, focusing on the actin dynamic signaling pathway.

TRPV4 channel activation induces the transition of venous and arterial endothelial cells toward a pro-inflammatory phenotype.

The Transient Receptor Potential Vanilloid 4 (TRPV4) of endothelial cells contributes to many important functions including the regulation of Ca homeostasis, cell volume, endothelial barrier permeability, and smooth muscle tone. However, its role in the transition of endothelial cells toward a pro-inflammatory phenotype has not been studied so far. Using both arterial and venous endothelial cells, we first show that the pharmacological activation of TRPV4 channels with GSK1016790A, a potent TRPV4 agonist, triggers robust and sustained Ca increases, which are blocked by both TRPV4 antagonists HC067047 and RN9893.

NAADP/SERCA3-Dependent Ca Stores Pathway Specifically Controls Early Autocrine ADP Secretion Potentiating Platelet Activation.

Rationale: Ca signaling is a key and ubiquitous actor of cell organization and its modulation controls many cellular responses. SERCAs (sarco-endoplasmic reticulum Ca-ATPases) pump Ca into internal stores that play a major role in the cytosolic Ca concentration rise upon cell activation. Platelets exhibit 2 types of SERCAs, SERCA2b and SERCA3 (SERCA3 deficient mice), which may exert specific roles, yet ill-defined.

Platelet Functions are Decreased in Obesity and Restored after Weight Loss: Evidence for a Role of the SERCA3-Dependent ADP Secretion Pathway.

In obesity, platelets are described as hyperactive, mainly based on increased platelet size and presence of pro-thrombotic plasmatic molecules. We explored platelet functions, including calcium signalling in obesity, and the effect of weight loss. We included 40 obese patients (women with body mass index [BMI] of ≥ 35 kg/m) who were to undergo gastric bypass surgery and 40 healthy lean subjects (women with BMI of < 25 kg/m) as a control group.

Filamin A Modulates Store-Operated Ca Entry by Regulating STIM1 (Stromal Interaction Molecule 1)-Orai1 Association in Human Platelets.

Objective: Here, we provide evidence for the role of FLNA (filamin A) in the modulation of store-operated calcium entry (SOCE).

Approach And Results: SOCE is a major mechanism for calcium influx controlled by the intracellular Ca stores. On store depletion, the endoplasmic reticulum calcium sensor STIM1 (stromal interaction molecule 1) redistributes into puncta at endoplasmic reticulum/plasma membrane junctions, a process supported by the cytoskeleton, where it interacts with the calcium channels; however, the mechanism for fine-tuning SOCE is not completely understood.

Full activation of mouse platelets requires ADP secretion regulated by SERCA3 ATPase-dependent calcium stores.

The role of the sarco-endoplasmic reticulum calcium (Ca(2+)) adenosine triphosphatase (ATPase) 3 (SERCA3) in platelet physiology remains poorly understood. Here, we show that SERCA3 knockout (SERCA3(-/-)) mice exhibit prolonged tail bleeding time and rebleeding. Thrombus formation was delayed both in arteries and venules in an in vivo ferric chloride-induced thrombosis model.

The Calcium Entry-Calcium Refilling Coupling.

Calcium ions (Ca(2+)) are versatile messengers that need to be tidily regulated in time and space in order to create a large number of signals. The coupling between Ca(2+) entry and Ca(2+) refilling is playing a central role in this Ca(2+) homeostasis. Since the capacitative Ca(2+) entry has been described, different mechanisms have been proposed in order to explain how the Ca(2+) entry could be under control of intracellular store Ca(2+) depletion.

Apelin: an antithrombotic factor that inhibits platelet function.

Apelin peptide and its receptor APJ are directly implicated in various physiological processes ranging from cardiovascular homeostasis to immune signaling. Here, we show that apelin is a key player in hemostasis with an ability to inhibit thrombin- and collagen-mediated platelet activation. Mice lacking apelin displayed a shorter bleeding time and a prothrombotic profile.

Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy.

The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats.

Expression of sarco (endo) plasmic reticulum calcium ATPase (SERCA) system in normal mouse cardiovascular tissues, heart failure and atherosclerosis.

Unlabelled: The sarco(endo)plasmic reticulum Ca(2+)ATPases (SERCA) system, a key regulator of calcium cycling and signaling, is composed of several isoforms. We aimed to characterize the expression of SERCA isoforms in mouse cardiovascular tissues and their modulation in cardiovascular pathologies (heart failure and/or atherosclerosis). Five isoforms (SERCA2a, 2b, 3a, 3b and 3c) were detected in the mouse heart and thoracic aorta.

A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.

Macrothrombocytopenias are the most important subgroup of inherited thrombocytopenias. This subgroup is particularly heterogeneous because the affected genes are involved in various functions such as cell signaling, cytoskeleton organization, and gene expression. Herein we describe the clinical and hematological features of a consanguineous family with a severe autosomal recessive macrothrombocytopenia associated with a thrombocytopathy inducing a bleeding tendency in the homozygous mutated patients.

CCR5 as a treatment target in pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PH), whether idiopathic or related to underlying diseases such as HIV infection, results from complex vessel remodeling involving both pulmonary artery smooth muscle cell (PA-SMC) proliferation and inflammation. CCR5, a coreceptor for cellular HIV-1 entry expressed on macrophages and vascular cells, may be involved in the pathogenesis of PH. Maraviroc is a new CCR5 antagonist designed to block HIV entry.

von Willebrand factor mutation promotes thrombocytopathy by inhibiting integrin αIIbβ3.

von Willebrand disease type 2B (vWD-type 2B) is characterized by gain-of-function mutations in von Willebrand factor (vWF) that enhance its binding to the glycoprotein Ib-IX-V complex on platelets. Patients with vWD-type 2B have a bleeding tendency that is linked to loss of vWF multimers and/or thrombocytopenia. In this study, we uncovered evidence that platelet dysfunction is a third possible mechanism for bleeding tendency.

Synergistic role of protein phosphatase inhibitor 1 and sarco/endoplasmic reticulum Ca2+ -ATPase in the acquisition of the contractile phenotype of arterial smooth muscle cells.

Background: Phenotypic modulation or switching of vascular smooth muscle cells from a contractile/quiescent to a proliferative/synthetic phenotype plays a key role in vascular proliferative disorders such as atherosclerosis and restenosis. Although several calcium handling proteins that control differentiation of smooth muscle cells have been identified, the role of protein phosphatase inhibitor 1 (I-1) in the acquisition or maintenance of the contractile phenotype modulation remains unknown.

Methods And Results: In human coronary arteries, I-1 and sarco/endoplasmic reticulum Ca2+ -ATPase expression is specific to contractile vascular smooth muscle cells.

Crucial role for endoplasmic reticulum stress during megakaryocyte maturation.

Objective: Apoptotic-like phase is an essential step for the platelet formation from megakaryocytes. How controlled is this signaling pathway remained poorly understood. The aim of this study was to determine whether endoplasmic reticulum (ER) stress-induced apoptosis occurs during thrombopoiesis.

R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.

Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence.

Benefit of SERCA2a gene transfer to vascular endothelial and smooth muscle cells: a new aspect in therapy of cardiovascular diseases.

Despite the great progress in cardiovascular health and clinical care along with marked decline in morbidity and mortality, cardiovascular diseases remain the leading causes of death and disability in the developed world. New therapeutic approaches, targeting not only systematic but also causal dysfunction, are ultimately needed to provide a valuable alternative for treatment of complex cardiovascular diseases. In heart failure, there are currently a number of trials that have been either completed or are ongoing targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) gene transfer in the context of heart failure.

The metabolic basis of adolescent idiopathic scoliosis: 2011 report of the "metabolic" workgroup of the Fondation Yves Cotrel.

Objective: The purpose of this review is to elucidate the metabolic processes involved in the pathogenesis of adolescent idiopathic scoliosis (AIS) in light of research by the present authors as well as current literature.

Methods: Pathogenetic mechanisms involved in AIS were modeled as (a) a form of neuromuscular scoliosis (in conjunction with an adverse mechanical environment such as bipedality), in which hormonal and other chemical factors act as regulators of skeletal muscle tone and function; (b) as a consequence of an abnormality in growth of the spinal column (in conjunction with an adverse mechanical environment such as bipedality), in which hormones and other chemical factors act as regulators of growth; and (c) as a mechanical failure of one side of the vertebral column due to a defect in trabecular formation or mineralization (in conjunction with an adverse mechanical environment such as bipedality); in which hormonal and other chemical factors act as regulators of bone formation, mineralization and/or resorption.

Results And Conclusion: Current evidence supporting these models individually or in combination is discussed.

Endoplasmic reticulum calcium pumps and cancer cell differentiation.

The endoplasmic reticulum (ER) is a major intracellular calcium storage pool and a multifunctional organelle that accomplishes several calcium-dependent functions involved in many homeostatic and signaling mechanisms. Calcium is accumulated in the ER by Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA)-type calcium pumps. SERCA activity can determine ER calcium content available for intra-ER functions and for calcium release into the cytosol, and can shape the spatiotemporal characteristics of calcium signals.

Endoplasmic reticulum calcium pumps and cancer.

Endoplasmic reticulum calcium homeostasis is involved in a multitude of signaling, as well as "house-keeping" functions that control cell growth, differentiation or apoptosis in every human/eukaryotic cell. Calcium is actively accumulated in the endoplasmic reticulum by Sarco/Endoplasmic Reticulum Calcium transport ATPases (SERCA enzymes). SERCA-dependent calcium transport is the only calcium uptake mechanism in this organelle, and therefore the regulation of SERCA function by the cell constitutes a key mechanism to adjust calcium homeostasis in the endoplasmic reticulum depending on the cell type and its state of differentiation.