Regulation Of Prostaglandin E2 Signaling By Cysteinyl Leukotrienes In Human Mast Cells
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Kondeti V; Duah E; Emory A; Thodeti C K; Paruchuri S
Faseb Journal
2013
2013-04
Journal Article or Conference Abstract Publication
n/a
Differential Regulation Of Cysteinyl Leukotriene Receptor Signaling By Protein Kinase C In Human Mast Cells
activation; antagonist; asthmatic subjects; desensitization; expression; hyperresponsiveness; intestinal epithelial-cells; proliferation; pulmonary inflammation; responses; Science & Technology - Other Topics
Cysteinyl leukotrienes (cys-LTs) are a group of lipid mediators that are potent bronchoconstrictors, powerful inducers of vascular leakage and potentiators of airway hyperresponsiveness. Cys-LTs play an essential role in asthma and are synthesized as well as activated in mast cells (MCs). Cys-LTs relay their effects mainly through two known GPCRs, CysLT(1)R and CysLT(2)R. Although protein kinase C (PKC) isoforms are implicated in the regulation of CysLT(1)R function, neither the role of PKCs in cys-LT-dependent MC inflammatory signaling nor the involvement of specific isoforms in MC function are known. Here, we show that PKC inhibition augmented LTD4 and LTE4-induced calcium influx through CysLT(1)R in MCs. In contrast, inhibition of PKCs suppressed c-fos expression as well MIP1 beta generation by cys-LTs. Interestingly, cys-LTs activated both PKC alpha and PKC epsilon isoforms in MC. However, knockdown of PKC alpha augmented cys-LT mediated calcium flux, while knockdown of PKC epsilon attenuated cys-LT induced c-fos expression and MIP1 beta generation. Taken together, these results demonstrate for the first time that cys-LT signaling downstream of CysLT(1)R in MCs is differentially regulated by two distinct PKCs which modulate inflammatory signals that have significant pathobiologic implications in allergic reactions and asthma pathology.
Kondeti V; Duah E; Al-Azzam N; Thodeti C K; Boyce J A; Paruchuri S
Plos One
2013
2013-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1371/journal.pone.0071536" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0071536</a>
A Novel Cross Talk Between Mechanosensitive Ion Channel Trpv4 And Vegfr2 In Human Endothelial Cells
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Kanugula A K; Adapala R K; Cappelli H C; Paruchrui S; Thodeti C K
Faseb Journal
2017
2017-04
Journal Article or Conference Abstract Publication
n/a
The Importance Of Polycystin 1 (pc1) In Endothelial Mitochondrial Bioenergetics
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Jones T J; Pung Y F; Adapala R K; Burke J R; Thodeti C K; Chilian W M
Faseb Journal
2012
2012-04
Journal Article or Conference Abstract Publication
n/a
Primary Cilia Regulates The Directional Migration And Barrier Integrity Of Endothelial Cells Through The Modulation Of Hsp27 Dependent Actin Cytoskeletal Organization
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Jones T J; Adapala R K; Geldenhuys W J; Bursley C; Nauli S; Thodeti C K
Faseb Journal
2011
2011-04
Journal Article or Conference Abstract Publication
n/a
Primary Cilia Regulates Endothelial Cell Directional Migration Through Hsp-27 Dependent Modulation Of Actin Cytoskeleton And Focal Adhesions
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Jones T J; Adapala R K; Bursley C; Nauli S M; Thodeti C K
Faseb Journal
2010
2010-04
Journal Article or Conference Abstract Publication
n/a
Glucocorticoid Signaling In Polycystin 1 (pc1) Null Endothelial Cells
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Jones T J; Adapala R K; Burke J R; Shubbar A S; Thodeti C K
Faseb Journal
2013
2013-04
Journal Article or Conference Abstract Publication
n/a
Upregulation Of Thrombospondin-1 Expression By Leptin In Vascular Smooth Muscle Cells: Role Of Mapk, Jak2 And Pkc Signaling Pathways
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Haney R M; Cuadra R H; Chavez R; Adapala R K; Thodeti C K; Raman P
Faseb Journal
2011
2011-04
Journal Article or Conference Abstract Publication
n/a
Knockout Of Type Vi Collagen Improves Cardiac Function And Remodeling Following Myocardial Infarction
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Luther D J; Thodeti C K; Weihrauch D; Patel H H; Niesman I R; Bonaldo P; Chilian W M; Meszaros J G
Faseb Journal
2012
2012-04
Journal Article or Conference Abstract Publication
n/a
Knockout Of Type Vi Collagen Preserves Mitochondrial Structure And Function Following Myocardial Infarction
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Luther D J; Patel H H; Niesman I R; Kang P T; Adapala R K; Thoppil R; Bonaldo P; Chilian W M; Chenn Y R; Thodeti C K; Meszaros J G
Faseb Journal
2013
2013-04
Journal Article or Conference Abstract Publication
n/a
Inflammatory Role Of Cysteinyl Leukotrienes In Human Vascular Endothelial Cells
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Duah E; Kondeti V; Adapala R K; Sanford J; Thodeti C K; Paruchuri S
Faseb Journal
2013
2013-04
Journal Article or Conference Abstract Publication
n/a
Cysteinyl Leukotrienes Regulate Endothelial Cell Inflammatory And Proliferative Signals Through Cyslt(2) And Cyslt(1) Receptors
atherosclerosis; barrier; dysfunction; expression; gamma; intestinal epithelial-cells; ischemia-reperfusion injury; migration; pathway; Science & Technology - Other Topics; thrombin
Duah E; Adapala R K; Al-Azzam N; Kondeti V; Gombedza F; Thodeti C K; Paruchuri S
Scientific Reports
2013
2013-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1038/srep03274" target="_blank" rel="noreferrer noopener">10.1038/srep03274</a>
Knockout of Type VI Collagen Preserves Mitochondrial Structure and Function Following Myocardial Infarction
ischemia; Extracellular matrix; Cardiovascular System & Cardiology; Hematology; cardiac remodeling
Meszaros J G; Luther D J; Kang P T; Chen Y R; Miller R L; Bonaldo P; Chilian W M; Thodeti C K
Circulation Research
2015
2015-07
Journal Article or Conference Abstract Publication
n/a
Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta 1 integrins
cytoskeleton; mechanotransduction; integrin; Cell Biology; Extracellular matrix; pathways; kinase; shear-stress; focal adhesions; living cells; stretch
Integrins are ubiquitous transmembrane mechanoreceptors that elicit changes in intracellular biochemistry in response to mechanical force application, but these alterations generally proceed over seconds to minutes. Stress-sensitive ion channels represent another class of mechanoreceptors that are activated much more rapidly (within msec), and recent findings suggest that calcium influx through Transient Receptor Potential Vanilloid-4 (TRPV4) channels expressed in the plasma membrane of bovine capillary endothelial cells is required for mechanical strain-induced changes in focal adhesion assembly, cell orientation and directional migration. However, whether mechanically stretching a cell's extracellular matrix (ECM) adhesions might directly activate cell surface ion channels remains unknown. Here we show that forces applied to beta 1 integrins result in ultra-rapid (within 4 msec) activation of calcium influx through TRPV4 channels. The TRPV4 channels were specifically activated by mechanical strain in the cytoskeletal backbone of the focal adhesion, and not by deformation of the lipid bilayer or submembranous cortical cytoskeleton alone. This early-immediate calcium signaling response required the distal region of the b1 integrin cytoplasmic tail that contains a binding site for the integrin-associated transmembrane CD98 protein, and external force application to CD98 within focal adhesions activated the same ultra-rapid calcium signaling response. Local direct strain-dependent activation of TRPV4 channels mediated by force transfer from integrins and CD98 may therefore enable compartmentalization of calcium signaling within focal adhesions that is critical for mechanical control of many cell behaviors that underlie cell and tissue development.
Matthews B D; Thodeti C K; Tytell J D; Mammoto A; Overby D R; Ingber D E
Integrative Biology
2010
2010
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1039/c0ib00034e" target="_blank" rel="noreferrer noopener">10.1039/c0ib00034e</a>
Actomyosin tension exerted on the nucleus through nesprin-1 connections influences endothelial cell adhesion, migration, and cyclic strain-induced reorientation (vol 99, pg 115, 2010)
Biophysics
Chancellor T J; Lee J; Thodeti C K; Lele T
Biophysical Journal
2010
2010-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.bpj.2010.07.033" target="_blank" rel="noreferrer noopener">10.1016/j.bpj.2010.07.033</a>
Actomyosin Tension Exerted on the Nucleus through Nesprin-1 Connections Influences Endothelial Cell Adhesion, Migration, and Cyclic Strain-Induced Reorientation
cytoskeleton; Biophysics; in-vitro; actin; envelope; polarization; dreifuss muscular-dystrophy; focal adhesions; lamin-a/c; mechanical stiffness; membrane protein; shape
Endothelial cell polarization and directional migration is required for angiogenesis. Polarization and motility requires not only local cytoskeletal remodeling but also the motion of intracellular organelles such as the nucleus. However, the physiological significance of nuclear positioning in the endothelial cell has remained largely unexplored. Here, we show that siRNA knockdown of nesprin-1, a protein present in the linker of nucleus to cytoskeleton complex, abolished the reorientation of endothelial cells in response to cyclic strain. Confocal imaging revealed that the nuclear height is substantially increased in nesprin-1 depleted cells, similar to myosin inhibited cells. Nesprin-1 depletion increased the number of focal adhesions and substrate traction while decreasing the speed of cell migration; however, there was no detectable change in nonmuscle myosin II activity in nesprin-1 deficient cells. Together, these results are consistent with a model in which the nucleus balances a portion of the actomyosin tension in the cell. In the absence of nesprin-1, actomyosin tension is balanced by the substrate, leading to abnormal adhesion, migration, and cyclic strain-induced reorientation.
Chancellor T J; Lee J; Thodeti C K; Lele T
Biophysical Journal
2010
2010-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.bpj.2010.04.011" target="_blank" rel="noreferrer noopener">10.1016/j.bpj.2010.04.011</a>
TRPV4 channels regulate vascular integrity through stabilization of VE-Cadherin junctions
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Cappelli H C; Amin V; Sharma P; Kanugula A K; Adapala R K; Meszaros J G; Paruchuri S K; Thodeti C K
Faseb Journal
2017
2017-04
Journal Article or Conference Abstract Publication
n/a
Modulation of Mast Cell Proliferative and Inflammatory Responses by Leukotriene D-4 and Stem Cell Factor Signaling Interactions
activation; Cell Biology; cysteinyl leukotrienes; fc-epsilon-ri; immune; induced airway hyperreactivity; innate; kit ligand; Physiology; protein-kinase-c; receptor; survival
Mast cells (MCs) are important effector cells in asthma and pulmonary inflammation, and their proliferation and maturation is maintained by stem cell factor (SCF) via its receptor, c-Kit. Cysteinyl leukotrienes (cys-LTs) are potent inflammatory mediators that signal through CysLT(1)R and CysLT(2)R located on the MC surface, and they enhance MC inflammatory responses. However, it is not known if SCF and cys-LTs cross-talk and influence MC hyperplasia and activation in inflammation. Here, we report the concerted effort of the growth factor SCF and the inflammatory mediator LTD4 in MC activation. Stimulation of MCs by LTD4 in the presence of SCF enhances c-Kit-mediated proliferative responses. Similarly, SCF synergistically enhances LTD4-induced calcium, c-fos expression and phosphorylation, as well as MIP1 generation in MCs. These findings suggest that integration of SCF and LTD4 signals may contribute to MC hyperplasia and hyper-reactivity during airway hyper-response and inflammation. J. Cell. Physiol. 230: 595-602, 2015. (c) 2014 Wiley Periodicals, Inc., A Wiley Company
Al-Azzam N; Kondeti V; Duah E; Gombedza F; Thodeti C K; Paruchuri S
Journal of Cellular Physiology
2015
2015-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/jcp.24777" target="_blank" rel="noreferrer noopener">10.1002/jcp.24777</a>
TRPV4 Channel Deletion Improves Cardiac Function and Remodeling Following Myocardial Infarction and Transverse Aortic Constriction via Modulation of Rho/MRTF-A Pathway
Cardiac hypertrophy; Cardiovascular System & Cardiology; Extracellular matrix; fibrosis; Hematology; Ion channels; Myocardial infarction
Adapala R K; Thoppil R; Cappelli H; Ohanyan V A; Luli J; Luther D J; Paruchuri S; Chilian W M; Meszaros J G; Thodeti C K
Circulation Research
2014
2014-12
Journal Article or Conference Abstract Publication
n/a
Protein Kinase C alpha mediates acetylcholine-induced TRPV4 activation in microvascular endothelial cells
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Adapala R K; Thalasila P K; Bratz I N; Meszaros G; Thodeti C K
Faseb Journal
2011
2011-04
Journal Article or Conference Abstract Publication
n/a
TRPV4 deletion improves cardiac function, structure and remodeling following myocardial infarction
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Adapala R K; Minasyan A; Kanugula A K; Cappelli H C; Paruchuri S; Meszaros J G; Thodeti C K
Faseb Journal
2017
2017-04
Journal Article or Conference Abstract Publication
n/a
Absence of TRPV4 protects heart from pressure-overload induced injury via inhibition of Rho/MRTF-A mediated cardiac fibrosis
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Adapala R K; Cappelli H C; Ohanyan V A; Lull J; Thoppil R J; Paruchuri S; Meszaros J G; Chilian W M; Thodeti C K
Faseb Journal
2016
2016-04
Journal Article or Conference Abstract Publication
n/a
Mechanosensitive Trpv4 Channels Mediate Cardiac Myofibroblast Differentitation
Cardiovascular System & Cardiology; Extracellular matrix; fibrosis; Ion channels; Myocardial infarction; Signal transduction
Adapala R; Luther D; Shah S; Meszaros J G; Chilian W M; Thodeti C K
Circulation
2011
2011-11
Journal Article or Conference Abstract Publication
n/a
TRPV4 Channel Activation Inhibits Tumor Endothelial Cell Proliferation and Migration Via Modulation of ERK1/2 pathway
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Thoppil R; Adapala R K; Cotman S; Paruchuri S; Chilian W M; Meszaros J G; Thodeti C K
Faseb Journal
2013
2013-04
Journal Article
n/a
TRPV4 channels regulate tumor angiogenesis through the modulation of Rho-dependent tumor endothelial cell mechanosensitivity
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Thodeti C K; Adapala R K; Ghosh K; Thoppil R; Dudley A C; Klagsbrun M; Chilian W; Ingber D
Faseb Journal
2012
2012-04
Journal Article
n/a
Mechanosensitive TRPV4 channels mediate cardiac fibroblast differentitation to myofibroblasts
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Thodeti C K; Adapala R K; Luther D J; Thoppil R; Chilian W; Meszaros J G
Faseb Journal
2012
2012-04
Journal Article
n/a
ROLE OF ARTERIAL TRPV1 CHANNELS IN ADRENERGIC SIGNALING
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Talasila P K; Adapala R K; Thodeti C K; Bratz I N
Faseb Journal
2011
2011-04
Journal Article
n/a
Trpv4 Calcium Channel Deficiency Protects Against Pulmonary Fibrosis In Mice And Abrogates Myofibroblast Differentiation
General & Internal Medicine; Respiratory System
Rahaman S O; Dominak L M; Paruchuri S; Southern B D; Abraham S; Niese K A; Scheraga R G; Ghosh S; Nagapasad S; Thodeti C K; Schilling W P; Tschumperlin D J; Zhang D X; Erzurum S C; Olman M A
American Journal of Respiratory and Critical Care Medicine
2014
2014
Journal Article
n/a
Endothelial Knockout of Polycystin 1 (PC1) Alters Mitochondrial Functions and Bioenergetics
Cardiovascular System & Cardiology; disease; Endothelial; Mitochondria; Reactive oxygen intermediates; Vascular
Pung Y F; Adapala R K; Burke J R; Geldenhuys W J; Chilian W M; Thodeti C K; Jones T J
Circulation
2012
2012-11
Journal Article
n/a
TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice
activation; cation channel trpv4; contraction; disease; fibroblasts; gene-expression; induced lung injury; mechanisms; pathogenesis; Research & Experimental Medicine; tgf-beta
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disorder with no effective medical treatments available. The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated TGF-beta; however, it is not clear how fibroblasts sense and transmit the mechanical signal(s) that promote differentiation into myofibroblasts. As transient receptor potential vanilloid 4 (TRPV4) channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether TRPV4 contributes to generation of myofibroblasts and/or experimental lung fibrosis. We determined that TRPV4 activity is upregulated in lung fibroblasts derived from patients with IPF. Moreover, TRPV4-deficient mice were protected from fibrosis. Furthermore, genetic ablation or pharmacological inhibition of TRPV4 function abrogated myofibroblast differentiation, which was restored by TRPV4 reintroduction. TRPV4 channel activity was elevated when cells were plated on matrices of increasing stiffness or on fibrotic lung tissue, and matrix stiffness-dependent myofibroblast differentiation was reduced in response to TRVP4 inhibition. TRPV4 activity modulated TGF-beta 1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the alpha-SMA transcription coactivator (MRTF-A). Together, these data indicate that TRPV4 activity mediates pulmonary fibrogenesis and suggest that manipulation of TRPV4 channel activity has potential as a therapeutic approach for fibrotic diseases.
Rahaman S O; Grove L M; Paruchuri S; Southern B D; Abraham S; Niese K A; Scheraga R G; Ghosh S; Thodeti C K; Zhang D X; Moran M M; Schilling W R; Tschumperlin D J; Olman M A
Journal of Clinical Investigation
2014
2014-12
Journal Article
<a href="http://doi.org/10.1172/jci75331" target="_blank" rel="noreferrer noopener">10.1172/jci75331</a>
Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.
Animals; Calcium Signaling/genetics; Carcinoma; Cell Line; Cell Proliferation/drug effects; Cisplatin/administration & dosage; Endothelium; Gene Expression Regulation; Humans; Leucine/administration & dosage/analogs & derivatives; Lewis Lung/drug therapy/*genetics/pathology; Mice; Neoplastic/drug effects; Neovascularization; Pathologic/drug therapy/*genetics/pathology; Sulfonamides/administration & dosage; TRPV Cation Channels/agonists/biosynthesis/*genetics; Tumor; Vascular Endothelial Growth Factor A/genetics; Vascular/drug effects/*pathology
Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.
Adapala R K; Thoppil R J; Ghosh K; Cappelli H C; Dudley A C; Paruchuri S; Keshamouni V; Klagsbrun M; Meszaros J G; Chilian W M; Ingber D E; Thodeti C K
Oncogene
2016
2016-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/onc.2015.83" target="_blank" rel="noreferrer noopener">10.1038/onc.2015.83</a>