Receptors and ionic transporters in nuclear membranes: new targets for therapeutical pharmacological interventions

2012 ◽  
Vol 90 (8) ◽  
pp. 953-965 ◽  
Author(s):  
Ghassan Bkaily ◽  
Levon Avedanian ◽  
Johny Al-Khoury ◽  
Lena Ahmarani ◽  
Claudine Perreault ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nuclear Membrane ◽  
Plasma Membranes ◽  
Vascular Endothelial Cells ◽  
Membrane Receptors ◽  
Ionic Homeostasis ◽  
Nuclear Membranes ◽  
Ionic Transporters ◽  
A Cell

Work from our group and other laboratories showed that the nucleus could be considered as a cell within a cell. This is based on growing evidence of the presence and role of nuclear membrane G-protein coupled receptors and ionic transporters in the nuclear membranes of many cell types, including vascular endothelial cells, endocardial endothelial cells, vascular smooth muscle cells, cardiomyocytes, and hepatocytes. The nuclear membrane receptors were found to modulate the functioning of ionic transporters at the nuclear level, and thus contribute to regulation of nuclear ionic homeostasis. Nuclear membranes of the mentioned types of cells possess the same ionic transporters; however, the type of receptors is cell-type dependent. Regulation of cytosolic and nuclear ionic homeostasis was found to be dependent upon a tight crosstalk between receptors and ionic transporters of the plasma membranes and those of the nuclear membrane. This crosstalk seems to be the basis for excitation–contraction coupling, excitation–secretion coupling, and excitation – gene expression coupling. Further advancement in this field will certainly shed light on the role of nuclear membrane receptors and transporters in health and disease. This will in turn enable the successful design of a new class of drugs that specifically target such highly vital nuclear receptors and ionic transporters.

Nuclear membrane receptors and channels as targets for drug development in cardiovascular diseasesThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 1 of a 2-part Special Issue).

2009 ◽  
Vol 87 (2) ◽  
pp. 108-119 ◽  
Author(s):  
Ghassan Bkaily ◽  
Levon Avedanian ◽  
Danielle Jacques
Keyword(s):  
Nuclear Membrane ◽  
Membrane Receptors ◽  
Heart Cells ◽  
Ionic Homeostasis ◽  
Life And Death ◽  
Ionic Transporters ◽  
Research Workshop ◽  
Modulation Of Gene Expression ◽  
Cardiovascular Cells ◽  
G Protein Coupled

The use of confocal microscopy has shown that the nucleus plays an important role in excitation–contraction and excitation–secretion coupling of several excitable and nonexcitable cardiovascular cells. It has shown that the nuclear membranes, like the sarcolemmal membrane, possess ionic transporters as well as G protein-coupled receptors (GPCRs), which play a major role in modulating both cytosolic and nuclear ionic homeostasis and nuclear signalling. During spontaneous contraction of heart cells, the increase in cytosolic Ca2+ was immediately followed by a transient increase in nuclear Ca2+. The nuclear Ca2+ rise during excitation–contraction and excitation–secretion coupling was both dependent and independent of changes in cytosolic Ca2+. Nuclear membrane GPCRs, such as those of angiotensin II, neuropeptide Y, and ET-1, were functional and contributed to modulation of nuclear ionic homeostasis via direct and (or) indirect modulation of nuclear membrane ionic transporters such as channels, pumps, and exchangers. The signalling of nuclear membrane GPCRs may also contribute to modulation of gene expression, which may regulate proliferation and remodelling of cells and, indeed, life and death. Direct or indirect targeting of nuclear membrane ionic transporters and GPCRs may constitute a new target for drug action.

Nuclear membrane receptors for ET-1 in cardiovascular function

2011 ◽  
Vol 300 (2) ◽  
pp. R251-R263 ◽  
Author(s):  
Ghassan Bkaily ◽  
Levon Avedanian ◽  
Johny Al-Khoury ◽  
Chantale Provost ◽  
Moni Nader ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Nuclear Membrane ◽  
Nuclear Translocation ◽  
Vascular Endothelial Cells ◽  
Cell Types ◽  
Membrane Receptors ◽  
Vascular Endothelial ◽  
Cell Type ◽  
Nuclear Membranes ◽  
New Generation

Plasma membrane endothelin type A (ETA) receptors are internalized and recycled to the plasma membrane, whereas endothelin type B (ETB) receptors undergo degradation and subsequent nuclear translocation. Recent studies show that G protein-coupled receptors (GPCRs) and ion transporters are also present and functional at the nuclear membranes of many cell types. Similarly to other GPCRs, ETA and ETB are present at both the plasma and nuclear membranes of several cardiovascular cell types, including human cardiac, vascular smooth muscle, endocardial endothelial, and vascular endothelial cells. The distribution and density of ETARs in the cytosol (including the cell membrane) and the nucleus (including the nuclear membranes) differ between these cell types. However, the localization and density of ET-1 and ETB receptors are similar in these cell types. The extracellular ET-1-induced increase in cytosolic ([Ca]c) and nuclear ([Ca]n) free Ca2+ is associated with an increase of cytosolic and nuclear reactive oxygen species. The extracellular ET-1-induced increase of [Ca]c and [Ca]n as well as intracellular ET-1-induced increase of [Ca]n are cell-type dependent. The type of ET-1 receptor mediating the extracellular ET-1-induced increase of [Ca]c and [Ca]n depends on the cell type. However, the cytosolic ET-1-induced increase of [Ca]n does not depend on cell type. In conclusion, nuclear membranes' ET-1 receptors may play an important role in overall ET-1 action. These nuclear membrane ET-1 receptors could be targets for a new generation of antagonists.

scholarly journals Emerging Role of AP-1 Transcription Factor JunB in Angiogenesis and Vascular Development

2021 ◽  
Vol 22 (6) ◽  
pp. 2804
Author(s):  
Yasuo Yoshitomi ◽  
Takayuki Ikeda ◽  
Hidehito Saito-Takatsuji ◽  
Hideto Yonekura
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Blood Vessel ◽  
Vascular Endothelial Cells ◽  
Vascular Development ◽  
Endothelial Cell Migration ◽  
Vascular Endothelial ◽  
Blood Vessel Formation ◽  
Vessel Formation

Blood vessels are essential for the formation and maintenance of almost all functional tissues. They play fundamental roles in the supply of oxygen and nutrition, as well as development and morphogenesis. Vascular endothelial cells are the main factor in blood vessel formation. Recently, research findings showed heterogeneity in vascular endothelial cells in different tissue/organs. Endothelial cells alter their gene expressions depending on their cell fate or angiogenic states of vascular development in normal and pathological processes. Studies on gene regulation in endothelial cells demonstrated that the activator protein 1 (AP-1) transcription factors are implicated in angiogenesis and vascular development. In particular, it has been revealed that JunB (a member of the AP-1 transcription factor family) is transiently induced in endothelial cells at the angiogenic frontier and controls them on tip cells specification during vascular development. Moreover, JunB plays a role in tissue-specific vascular maturation processes during neurovascular interaction in mouse embryonic skin and retina vasculatures. Thus, JunB appears to be a new angiogenic factor that induces endothelial cell migration and sprouting particularly in neurovascular interaction during vascular development. In this review, we discuss the recently identified role of JunB in endothelial cells and blood vessel formation.

The recombinant lectin-like domain of thrombomodulin inhibits angiogenesis through interaction with Lewis Y antigen

Blood ◽  
2012 ◽  
Vol 119 (5) ◽  
pp. 1302-1313 ◽  
Author(s):  
Cheng-Hsiang Kuo ◽  
Po-Ku Chen ◽  
Bi-Ing Chang ◽  
Meng-Chen Sung ◽  
Chung-Sheng Shi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Egf Receptor ◽  
Tube Formation ◽  
Endothelial Tube Formation ◽  
A Cell ◽  
Lewis Y ◽  
Tm Domain

AbstractLewis Y Ag (LeY) is a cell-surface tetrasaccharide that participates in angiogenesis. Recently, we demonstrated that LeY is a specific ligand of the recombinant lectin-like domain of thrombomodulin (TM). However, the biologic function of interaction between LeY and TM in endothelial cells has never been investigated. Therefore, the role of LeY in tube formation and the role of the recombinant lectin-like domain of TM—TM domain 1 (rTMD1)—in antiangiogenesis were investigated. The recombinant TM ectodomain exhibited lower angiogenic activity than did the recombinant TM domains 2 and 3. rTMD1 interacted with soluble LeY and membrane-bound LeY and inhibited soluble LeY-mediated chemotaxis of endothelial cells. LeY was highly expressed on membrane ruffles and protrusions during tube formation on Matrigel. Blockade of LeY with rTMD1 or Ab against LeY inhibited endothelial tube formation in vitro. Epidermal growth factor (EGF) receptor in HUVECs was LeY modified. rTMD1 inhibited EGF receptor signaling, chemotaxis, and tube formation in vitro, and EGF-mediated angiogenesis and tumor angiogenesis in vivo. We concluded that LeY is involved in vascular endothelial tube formation and rTMD1 inhibits angiogenesis via interaction with LeY. Administration of rTMD1 or recombinant adeno-associated virus vector carrying TMD1 could be a promising antiangiogenesis strategy.

scholarly journals Shear stress augments mitochondrial ATP generation that triggers ATP release and Ca2+ signaling in vascular endothelial cells

2018 ◽  
Vol 315 (5) ◽  
pp. H1477-H1485 ◽  
Author(s):  
Kimiko Yamamoto ◽  
Hiromi Imamura ◽  
Joji Ando
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Vascular Endothelial Cells ◽  
Critical Role ◽  
Atp Release ◽  
Vascular Endothelial ◽  
The Novel ◽  
Caveolin 1 ◽  
Atp Generation

Vascular endothelial cells (ECs) sense and transduce hemodynamic shear stress into intracellular biochemical signals, and Ca2+ signaling plays a critical role in this mechanotransduction, i.e., ECs release ATP in the caveolae in response to shear stress and, in turn, the released ATP activates P2 purinoceptors, which results in an influx into the cells of extracellular Ca2+. However, the mechanism by which the shear stress evokes ATP release remains unclear. Here, we demonstrated that cellular mitochondria play a critical role in this process. Cultured human pulmonary artery ECs were exposed to controlled levels of shear stress in a flow-loading device, and changes in the mitochondrial ATP levels were examined by real-time imaging using a fluorescence resonance energy transfer-based ATP biosensor. Immediately upon exposure of the cells to flow, mitochondrial ATP levels increased, which was both reversible and dependent on the intensity of shear stress. Inhibitors of the mitochondrial electron transport chain and ATP synthase as well as knockdown of caveolin-1, a major structural protein of the caveolae, abolished the shear stress-induced mitochondrial ATP generation, resulting in the loss of ATP release and influx of Ca2+ into the cells. These results suggest the novel role of mitochondria in transducing shear stress into ATP generation: ATP generation leads to ATP release in the caveolae, triggering purinergic Ca2+ signaling. Thus, exposure of ECs to shear stress seems to activate mitochondrial ATP generation through caveola- or caveolin-1-mediated mechanisms. NEW & NOTEWORTHY The mechanism of how vascular endothelial cells sense shear stress generated by blood flow and transduce it into functional responses remains unclear. Real-time imaging of mitochondrial ATP demonstrated the novel role of endothelial mitochondria as mechanosignaling organelles that are able to transduce shear stress into ATP generation, triggering ATP release and purinoceptor-mediated Ca2+ signaling within the cells.

Pulmonary reduction of an intravascular redox polymer

2001 ◽  
Vol 280 (6) ◽  
pp. L1290-L1299 ◽  
Author(s):  
Said H. Audi ◽  
Robert D. Bongard ◽  
Yoshiyuki Okamoto ◽  
Marilyn P. Merker ◽  
David L. Roerig ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Superoxide Dismutase ◽  
Electron Transport ◽  
Kinetic Model ◽  
Electron Acceptors ◽  
Redox Polymer ◽  
Pulmonary Endothelial Cells ◽  
Equilibrium Level ◽  
A Cell

Pulmonary endothelial cells in culture reduce external electron acceptors via transplasma membrane electron transport (TPMET). In studying endothelial TPMET in intact lungs, it is difficult to exclude intracellular reduction and reducing agents released by the lung. Therefore, we evaluated the role of endothelial TPMET in the reduction of a cell-impermeant redox polymer, toluidine blue O polyacrylamide (TBOP+), in intact rat lungs. When added to the perfusate recirculating through the lungs, the venous effluent TBOP+concentration decreased to an equilibrium level reflecting TBOP+ reduction and autooxidation of its reduced (TBOPH) form. Adding superoxide dismutase (SOD) to the perfusate increased the equilibrium TBOP+ concentration. Kinetic analysis indicated that the SOD effect could be attributed to elimination of the superoxide product of TBOPH autooxidation rather than of superoxide released by the lungs, and experiments with lung-conditioned perfusate excluded release of other TBOP+ reductants in sufficient quantities to cause significant TBOP+ reduction. Thus the results indicate that TBOP+ reduction is via TPMET and support the utility of TBOP+ and the kinetic model for investigating TPMET mechanisms and their adaptations to physiological and pathophysiological stresses in the intact lung.

scholarly journals Human vascular adhesion protein 1 (VAP-1) is a unique sialoglycoprotein that mediates carbohydrate-dependent binding of lymphocytes to endothelial cells.

1996 ◽  
Vol 183 (2) ◽  
pp. 569-579 ◽  
Author(s):  
M Salmi ◽  
S Jalkanen
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vascular Endothelial Cells ◽  
Lymphoid Tissues ◽  
Vascular Endothelial ◽  
Adhesion Protein ◽  
Culture Model ◽  
Vascular Adhesion ◽  
Vascular Adhesion Protein 1

The regulated interactions of leukocytes with vascular endothelial cells are crucial in controlling leukocyte traffic between blood and tissues. Vascular adhesion protein-1 (VAP-1) is a novel, human endothelial cell molecule that mediates tissue-selective lymphocyte binding. Two species (90 and 170 kD) of VAP-1 exist in lymphoid tissues. Glycosidase digestions revealed that the mature 170-kD form of VAP-1 expressed on the lumenal surfaces of vessels is a heavily sialylated glycoprotein. The sialic acids are indispensable for the function of VAP-1, since the desialylated form of VAP-1 no longer mediates lymphocyte binding. We also show that L-selectin is not required for binding of activated lymphocytes to VAP-1 under conditions of shear stress. The 90-kD form of VAP-1 was only seen in an organ culture model, and may represent a monomeric or proteolytic form of the larger species. These data indicate that L-selectin negative lymphocytes can bind to tonsillar venules via the VAP- 1-mediated pathway. Moreover, our findings extend the role of carbohydrate-mediated binding in lymphocyte-endothelial cell interactions beyond the known selectins. In conclusion, VAP-1 naturally exists as a 170-kD sialoglycoprotein that uses sialic acid residues to interact with its counter-receptors on lymphocytes under nonstatic conditions.

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