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Tissue inflammation and nitric oxide-mediated alterations in cardiovascular function are major determinants of endotoxin-induced insulin resistance.
House LM, Morris RT, Barnes TM, Lantier L, Cyphert TJ, McGuinness OP, Otero YF
(2015) Cardiovasc Diabetol 14: 56
MeSH Terms: Animals, Arterial Pressure, Cardiac Output, Chemokine CCL2, Echocardiography, Endothelium-Dependent Relaxing Factors, Gene Expression, Glucose, Glucose Clamp Technique, Heart, Inflammation, Insulin Resistance, Interleukin-6, Lipopolysaccharides, Mice, Mice, Knockout, Microspheres, Muscle Cells, Muscle, Skeletal, Nitric Oxide, Nitric Oxide Synthase Type II, RNA, Messenger, Regional Blood Flow, Serpin E2, Tumor Necrosis Factor-alpha
Show Abstract · Added July 30, 2015
BACKGROUND - Endotoxin (i.e. LPS) administration induces a robust inflammatory response with accompanying cardiovascular dysfunction and insulin resistance. Overabundance of nitric oxide (NO) contributes to the vascular dysfunction. However, inflammation itself also induces insulin resistance in skeletal muscle. We sought to investigate whether the cardiovascular dysfunction induced by increased NO availability without inflammatory stress can promote insulin resistance. Additionally, we examined the role of inducible nitric oxide synthase (iNOS or NOS2), the source of the increase in NO availability, in modulating LPS-induced decrease in insulin-stimulated muscle glucose uptake (MGU).
METHODS - The impact of NO donor infusion on insulin-stimulated whole-body and muscle glucose uptake (hyperinsulinemic-euglycemic clamps), and the cardiovascular system was assessed in chronically catheterized, conscious mice wild-type (WT) mice. The impact of LPS on insulin action and the cardiovascular system were assessed in WT and global iNOS knockout (KO) mice. Tissue blood flow and cardiac function were assessed using microspheres and echocardiography, respectively. Insulin signaling activity, and gene expression of pro-inflammatory markers were also measured.
RESULTS - NO donor infusion decreased mean arterial blood pressure, whole-body glucose requirements, and MGU in the absence of changes in skeletal muscle blood flow. LPS lowered mean arterial blood pressure and glucose requirements in WT mice, but not in iNOS KO mice. Lastly, despite an intact inflammatory response, iNOS KO mice were protected from LPS-mediated deficits in cardiac output. LPS impaired MGU in vivo, regardless of the presence of iNOS. However, ex vivo, insulin action in muscle obtained from LPS treated iNOS KO animals was protected.
CONCLUSION - Nitric oxide excess and LPS impairs glycemic control by diminishing MGU. LPS impairs MGU by both the direct effect of inflammation on the myocyte, as well as by the indirect NO-driven cardiovascular dysfunction.
0 Communities
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2 Resources
25 MeSH Terms
Suppression of spontaneous ca elevations prevents atrial fibrillation in calsequestrin 2-null hearts.
Faggioni M, Savio-Galimberti E, Venkataraman R, Hwang HS, Kannankeril PJ, Darbar D, Knollmann BC
(2014) Circ Arrhythm Electrophysiol 7: 313-20
MeSH Terms: Animals, Atrial Fibrillation, Calcium, Calsequestrin, Cardiac Pacing, Artificial, Disease Models, Animal, Mice, Mice, Knockout, Muscle Cells, Propafenone, Treatment Outcome, Voltage-Gated Sodium Channel Blockers
Show Abstract · Added May 29, 2014
BACKGROUND - Atrial fibrillation (AF) risk has been associated with leaky ryanodine receptor 2 (RyR2) Ca release channels. Patients with mutations in RyR2 or in the sarcoplasmic reticulum Ca-binding protein calsequestrin 2 (Casq2) display an increased risk for AF. Here, we examine the underlying mechanisms of AF associated with loss of Casq2 and test mechanism-based drug therapy.
METHODS AND RESULTS - Compared with wild-type Casq2+/+ mice, atrial burst pacing consistently induced atrial flutter or AF in Casq2-/- mice and in isolated Casq2-/- hearts. Atrial optical voltage maps obtained from isolated hearts revealed multiple independent activation sites arising predominantly from the pulmonary vein region. Ca and voltage mapping demonstrated diastolic subthreshold spontaneous Ca elevations (SCaEs) and delayed afterdepolarizations whenever the pacing train failed to induce AF. The dual RyR2 and Na channel inhibitor R-propafenone (3 ╬╝mol/L) significantly reduced frequency and amplitude of SCaEs and delayed afterdepolarizations in atrial myocytes and intact atria and prevented induction of AF. In contrast, the S-enantiomer of propafenone, an equipotent Na channel blocker but much weaker RyR2 inhibitor, did not reduce SCaEs and delayed afterdepolarizations and failed to prevent AF.
CONCLUSIONS - Loss of Casq2 increases risk of AF by promoting regional SCaEs and delayed afterdepolarizations in atrial tissue, which can be prevented by RyR2 inhibition with R-propafenone. Targeting AF caused by leaky RyR2 Ca channels with R-propafenone may be a more mechanism-based approach to treating this common arrhythmia.
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2 Members
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12 MeSH Terms
Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance.
Bonner JS, Lantier L, Hasenour CM, James FD, Bracy DP, Wasserman DH
(2013) Diabetes 62: 572-80
MeSH Terms: Animals, Blood Glucose, Capillaries, Gene Deletion, Hypoglycemic Agents, Insulin, Insulin Resistance, Mice, Mice, Inbred C57BL, Muscle Cells, Muscle, Skeletal, Myocardium, Signal Transduction, Vascular Endothelial Growth Factor A
Show Abstract · Added March 18, 2013
Muscle insulin resistance is associated with a reduction in vascular endothelial growth factor (VEGF) action and muscle capillary density. We tested the hypothesis that muscle capillary rarefaction critically contributes to the etiology of muscle insulin resistance in chow-fed mice with skeletal and cardiac muscle VEGF deletion (mVEGF(-/-)) and wild-type littermates (mVEGF(+/+)) on a C57BL/6 background. The mVEGF(-/-) mice had an ~60% and ~50% decrease in capillaries in skeletal and cardiac muscle, respectively. The mVEGF(-/-) mice had augmented fasting glucose turnover. Insulin-stimulated whole-body glucose disappearance was blunted in mVEGF(-/-) mice. The reduced peripheral glucose utilization during insulin stimulation was due to diminished in vivo cardiac and skeletal muscle insulin action and signaling. The decreased insulin-stimulated muscle glucose uptake was independent of defects in insulin action at the myocyte, suggesting that the impairment in insulin-stimulated muscle glucose uptake was due to poor muscle perfusion. The deletion of VEGF in cardiac muscle did not affect cardiac output. These studies emphasize the importance for novel therapeutic approaches that target the vasculature in the treatment of insulin-resistant muscle.
2 Communities
4 Members
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14 MeSH Terms
Bves directly interacts with GEFT, and controls cell shape and movement through regulation of Rac1/Cdc42 activity.
Smith TK, Hager HA, Francis R, Kilkenny DM, Lo CW, Bader DM
(2008) Proc Natl Acad Sci U S A 105: 8298-303
MeSH Terms: Animals, Cell Adhesion Molecules, Cell Movement, Cell Shape, Cytoplasm, DNA Mutational Analysis, Guanine Nucleotide Exchange Factors, Mice, Muscle Cells, Muscle Proteins, NIH 3T3 Cells, Neuropeptides, Protein Interaction Domains and Motifs, Rho Guanine Nucleotide Exchange Factors, Sequence Deletion, Two-Hybrid System Techniques, cdc42 GTP-Binding Protein, rac GTP-Binding Proteins, rac1 GTP-Binding Protein
Show Abstract · Added September 28, 2015
Bves is an integral membrane protein with no determined function and no homology to proteins outside of the Popdc family. It is widely expressed throughout development in myriad organisms. Here, we demonstrate an interaction between Bves and guanine nucleotide exchange factor T (GEFT), a GEF for Rho-family GTPases. This interaction represents the first identification of any protein that has a direct physical interaction with any member of the Popdc family. Bves and GEFT are shown to colocalize in adult skeletal muscle. We also demonstrate that exogenous expression of Bves reduces Rac1 and Cdc42 activity levels while not affecting levels of active RhoA. Consistent with a repression of Rac1 and Cdc42 activity, we show changes in speed of cell locomotion and cell roundness also result from exogenous expression of Bves. Modulation of Rho-family GTPase signaling by Bves would be highly consistent with previously described phenotypes occurring upon disruption of Bves function in a wide variety of model systems. Therefore, we propose Bves as a novel regulator of the Rac1 and Cdc42 signaling cascades.
1 Communities
1 Members
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19 MeSH Terms
Temporal dissociation of frequency-dependent acceleration of relaxation and protein phosphorylation by CaMKII.
Huke S, Bers DM
(2007) J Mol Cell Cardiol 42: 590-9
MeSH Terms: Animals, Calcium-Binding Proteins, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Enzyme Inhibitors, Heart, Muscle Cells, Phosphoric Monoester Hydrolases, Phosphorylation, Phosphoserine, Phosphothreonine, Rats, Ryanodine Receptor Calcium Release Channel, Time Factors
Show Abstract · Added May 27, 2014
Frequency-dependent acceleration of relaxation (FDAR) is an important intrinsic mechanism that allows for diastolic filling of the ventricle at higher heart rates, yet its molecular mechanism is still not understood. Previous studies showed that FDAR is dependent on functional sarcoplasmic reticulum (SR) and can be abolished by phosphatase or by Ca/CaM kinase (CaMKII) inhibition. Additionally, CaMKII activity/autophosphorylation has been shown to be frequency-dependent. Thus, we tested the hypothesis that CaMKII phosphorylation of SR Ca(2+)-handling proteins (Phospholamban (PLB), Ca(2+) release channel (RyR)) mediates FDAR. Here we show that FDAR occurs abruptly in fluo-4 loaded isolated rat ventricular myocytes when frequency is raised from 0.1 to 2 Hz. The effect is essentially complete within four beats (2 s) with the tau of [Ca(2+)](i) decline decreasing by 42+/-3%. While there is a detectable increase in PLB Thr-17 and RyR Ser-2814 phosphorylation, the increase is quantitatively small (PLB<5%, RyR approximately 8%) and the time-course is clearly delayed with regard to FDAR. The low substrate phosphorylation indicates that pacing of myocytes only mildly activates CaMKII and consistent with this CaMKIIdelta autophosphorylation did not increase with pacing alone. However, in the presence of phosphatase 1 inhibition pacing triggered a net-increase in autophosphorylated CaMKII and also greatly enhanced PLB and RyR phosphorylation. We conclude that FDAR does not rely on phosphorylation of PLB or RyR. Even though CaMKII does become activated when myocytes are paced, phosphatases immediately antagonize CaMKII action, limit substrate phosphorylation and also prevent sustained CaMKII autophosphorylation (thereby suppressing global CaMKII effects).
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14 MeSH Terms
Involvement of p120 catenin in myopodial assembly and nerve-muscle synapse formation.
Madhavan R, Zhao XT, Reynolds AB, Peng HB
(2006) J Neurobiol 66: 1511-27
MeSH Terms: Agrin, Animals, Blotting, Western, Catenins, Cell Adhesion Molecules, Cells, Cultured, Coculture Techniques, Embryo, Nonmammalian, Gene Expression, Gene Expression Regulation, Green Fluorescent Proteins, Humans, Muscle Cells, Neuromuscular Junction, Neurons, Phosphoproteins, Pseudopodia, Receptors, Cholinergic, Time Factors, Tyrosine, Xenopus
Show Abstract · Added March 5, 2014
At developing neuromuscular junctions (NMJs), muscles initially contact motor axons by microprocesses, or myopodia, which are induced by nerves and nerve-secreted agrin, but it is unclear how myopodia are assembled and how they influence synaptic differentiation at the NMJ. Here, we report that treatment of cultured muscle cells with agrin transiently depleted p120 catenin (p120ctn) from cadherin junctions in situ, and increased the tyrosine phosphorylation and decreased the cadherin-association of p120ctn in cell extracts. Whereas ectopic expression of wild-type p120ctn in muscle generated myopodia in the absence of agrin, expression of a specific dominant-negative mutant form of p120ctn, which blocks filopodial assembly in nonmuscle cells, suppressed nerve- and agrin-induction of myopodia. Significantly, approaching neurites triggered reduced acetylcholine receptor (AChR) clustering along the edges of muscle cells expressing mutant p120ctn than of control cells, although the ability of the mutant cells to cluster AChRs was itself normal. Our results indicate a novel role of p120ctn in agrin-induced myopodial assembly and suggest that myopodia increase muscle-nerve contacts and muscle's access to neural agrin to promote NMJ formation.
Copyright 2006 Wiley Periodicals, Inc.
1 Communities
1 Members
0 Resources
21 MeSH Terms
Transforming growth factor beta regulates the expression of the M2 muscarinic receptor in atrial myocytes via an effect on RhoA and p190RhoGAP.
Park HJ, Ward SM, Desgrosellier JS, Georgescu SP, Papageorge AG, Zhuang X, Barnett JV, Galper JB
(2006) J Biol Chem 281: 19995-20002
MeSH Terms: Amides, Animals, Carrier Proteins, Cells, Cultured, Chick Embryo, Enzyme Inhibitors, Gene Expression Regulation, Heart Atria, Muscle Cells, Promoter Regions, Genetic, Pyridines, Receptor, Muscarinic M2, Signal Transduction, Transforming Growth Factor beta, rhoA GTP-Binding Protein
Show Abstract · Added February 21, 2016
Transforming growth factor beta (TGFbeta) signaling is involved in the development and regulation of multiple organ systems and cellular signaling pathways. We recently demonstrated that TGFbeta regulates the response of atrial myocytes to parasympathetic stimulation. Here, TGFbeta(1) is shown to inhibit expression of the M(2) muscarinic receptor (M(2)), which plays a critical role in the parasympathetic response of the heart. This effect is mimicked by overexpression of a dominant negative mutant of RhoA and by the RhoA kinase inhibitor Y27632, whereas adenoviral expression of a dominant activating-RhoA reverses TGFbeta inhibition of M(2) expression. TGFbeta(1) also mediates a decrease in GTP-bound RhoA and a reciprocal increase in the expression of the RhoA GTPase-activating protein, p190RhoGAP, whereas total RhoA is unchanged. Inhibition of M(2) promoter activity by TGFbeta(1) is mimicked by overexpression of p190RhoGAP, whereas a dominant negative mutant of p190RhoGAP reverses this effect of TGFbeta(1). In contrast to atrial myocytes, in mink lung epithelial cells, in which TGFbeta signaling through activation of RhoA has been previously identified, TGFbeta(1) stimulated an increase in GTP-bound RhoA in association with a reciprocal decrease in the expression of p190RhoGAP. Both effects demonstrated a similar dose dependence on TGFbeta(1). Thus TGFbeta regulation of M(2) muscarinic receptor expression is dependent on RhoA, and TGFbeta regulation of p190RhoGAP expression may be a cell type-specific mechanism for TGFbeta signaling through RhoA.
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15 MeSH Terms
Identification of S-nitrosylation motifs by site-specific mapping of the S-nitrosocysteine proteome in human vascular smooth muscle cells.
Greco TM, Hodara R, Parastatidis I, Heijnen HF, Dennehy MK, Liebler DC, Ischiropoulos H
(2006) Proc Natl Acad Sci U S A 103: 7420-5
MeSH Terms: Amino Acid Sequence, Cells, Cultured, Cysteine, Humans, Mass Spectrometry, Microscopy, Electron, Transmission, Microscopy, Immunoelectron, Molecular Sequence Data, Muscle Cells, Muscle, Smooth, Vascular, Nitrogen, Peptides, Proteome, S-Nitrosothiols
Show Abstract · Added March 20, 2014
S-nitrosylation, the selective modification of cysteine residues in proteins to form S-nitrosocysteine, is a major emerging mechanism by which nitric oxide acts as a signaling molecule. Even though nitric oxide is intimately involved in the regulation of vascular smooth muscle cell functions, the potential protein targets for nitric oxide modification as well as structural features that underlie the specificity of protein S-nitrosocysteine formation in these cells remain unknown. Therefore, we used a proteomic approach using selective peptide capturing and site-specific adduct mapping to identify the targets of S-nitrosylation in human aortic smooth muscle cells upon exposure to S-nitrosocysteine and propylamine propylamine NONOate. This strategy identified 20 unique S-nitrosocysteine-containing peptides belonging to 18 proteins including cytoskeletal proteins, chaperones, proteins of the translational machinery, vesicular transport, and signaling. Sequence analysis of the S-nitrosocysteine-containing peptides revealed the presence of acid/base motifs, as well as hydrophobic motifs surrounding the identified cysteine residues. High-resolution immunogold electron microscopy supported the cellular localization of several of these proteins. Interestingly, seven of the 18 proteins identified are localized within the ER/Golgi complex, suggesting a role for S-nitrosylation in membrane trafficking and ER stress response in vascular smooth muscle.
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1 Members
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14 MeSH Terms
Heat shock protein 90 stabilization of ErbB2 expression is disrupted by ATP depletion in myocytes.
Peng X, Guo X, Borkan SC, Bharti A, Kuramochi Y, Calderwood S, Sawyer DB
(2005) J Biol Chem 280: 13148-52
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Animals, Benzoquinones, Cell Proliferation, Cells, Cultured, Dose-Response Relationship, Drug, Glycolysis, HSP90 Heat-Shock Proteins, Immunoprecipitation, Lactams, Macrocyclic, Ligands, Male, Muscle Cells, Myocytes, Cardiac, Oxygen Consumption, Phosphorylation, Protein Binding, Quinones, Rats, Rats, Sprague-Dawley, Receptor, ErbB-2, Receptors, Adrenergic, beta, Time Factors
Show Abstract · Added March 5, 2014
Heat shock protein (Hsp) 90 is a ubiquitously expressed chaperone that stabilizes expression of multiple signaling kinases involved in growth regulation, including ErbB2, Raf-1, and Akt. The chaperone activity of Hsp90 requires ATP, which binds with approximately 10-fold lower affinity than ADP. This suggests that Hsp90 may be a physiological ATP sensor, regulating the stability of growth signaling cascades in relation to cellular energy charge. Here we show that lowering ATP concentration by inhibiting glycolysis or mitochondrial respiration in isolated myocytes triggers rapid dissociation of Hsp90 from ErbB2 and degradation of ErbB2 along with other client proteins. The effect of disrupting Hsp90 chaperone activity by ATP depletion was similar to the effect of the pharmacological Hsp90 inhibitor geldanamycin. ATP depletion-induced disruption of Hsp90 chaperone activity was associated with cellular resistance to growth factor activation of intracellular signaling. ErbB2 degradation was also induced by the physiological stress of beta-adrenergic receptor stimulation in electrically stimulated cells. These results support a role for Hsp90 as an ATP sensor that modulates tissue growth factor responsiveness under metabolically stressed conditions and provide a novel mechanism by which cellular responsiveness to growth factor stimulation is modulated by cellular energy charge.
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24 MeSH Terms
Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes.
Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, Eppenberger HM, Suter TM, Liao R, Sawyer DB
(2004) J Biol Chem 279: 8290-9
MeSH Terms: Animals, Anthracyclines, Antibiotics, Antineoplastic, Apoptosis, Calpain, Caspase 3, Caspase Inhibitors, Caspases, Cells, Cultured, Connectin, Doxorubicin, Enzyme Activation, Enzyme Inhibitors, Heart Ventricles, Male, Muscle Cells, Muscle Proteins, Myocardium, Necrosis, Protein Kinases, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 5, 2014
Titin, the largest myofilament protein, serves as a template for sarcomere assembly and acts as a molecular spring to contribute to diastolic function. Titin is known to be extremely susceptible to calcium-dependent protease degradation in vitro. We hypothesized that titin degradation is an early event in doxorubicin-induced cardiac injury and that titin degradation occurs by activation of the calcium-dependent proteases, the calpains. Treatment of cultured adult rat cardiomyocytes with 1 or 3 micromol/liter doxorubicin for 24 h resulted in degradation of titin in myocyte lysates, which was confirmed by a reduction in immunostaining of an antibody to the spring-like (PEVK) domain of titin at the I-band of the sarcomere. The elastic domain of titin appears to be most susceptible to proteolysis because co-immunostaining with an antibody to titin at the M-line was preserved, suggesting targeted proteolysis of the spring-like domain of titin. Doxorubicin treatment for 1 h resulted in approximately 3-fold increase in calpain activity, which remained elevated at 48 h. Co-treatment with calpain inhibitors resulted in preservation of titin, reduction in myofibrillar disarray, and attenuation of cardiomyocyte necrosis but not apoptosis. Co-treatment with a caspase inhibitor did not prevent the degradation of titin, which precludes caspase-3 as an early mechanism of titin proteolysis. We conclude that calpain activation is an early event after doxorubicin treatment in cardiomyocytes and appears to target the degradation of titin. Proteolysis of the spring-like domain of titin may predispose cardiomyocytes to diastolic dysfunction, myofilament instability, and cell death by necrosis.
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22 MeSH Terms