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Nanotechnology Enabled Modulation of Signaling Pathways Affects Physiologic Responses in Intact Vascular Tissue.
Hocking KM, Evans BC, Komalavilas P, Cheung-Flynn J, Duvall CL, Brophy CM
(2019) Tissue Eng Part A 25: 416-426
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Blood Vessels, Calcium, Gene Silencing, Heat-Shock Proteins, Humans, Micelles, Muscle Contraction, Muscle, Smooth, Nanoparticles, Nanotechnology, Peptides, Polymerization, RNA, Small Interfering, Rats, Signal Transduction, Static Electricity
Show Abstract · Added April 10, 2019
IMPACT STATEMENT - Subarachnoid hemorrhage (SAH) is associated with vasospasm that is refractory to traditional vasodilators, and inhibition of vasospasm after SAH remains a large unmet clinical need. SAH causes changes in the phosphorylation state of the small heat shock proteins (HSPs), HSP20 and HSP27, in the vasospastic vessels. In this study, the levels of HSP27 and HSP20 were manipulated using nanotechnology to mimic the intracellular phenotype of SAH-induced vasospasm, and the effect of this manipulation was tested on vasomotor responses in intact tissues. This work provides insight into potential therapeutic targets for the development of more effective treatments for SAH induced vasospasm.
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19 MeSH Terms
Adenosine triphosphate as a molecular mediator of the vascular response to injury.
Guth CM, Luo W, Jolayemi O, Chadalavada KS, Komalavilas P, Cheung-Flynn J, Brophy CM
(2017) J Surg Res 216: 80-86
MeSH Terms: Adenosine Triphosphate, Animals, Aorta, Abdominal, Biomarkers, Biomechanical Phenomena, Blotting, Western, Female, Muscle Contraction, Rats, Rats, Sprague-Dawley, Receptors, Purinergic P2X7, Stress, Mechanical, Vascular System Injuries, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added May 22, 2018
BACKGROUND - Human saphenous veins used for arterial bypass undergo stretch injury at the time of harvest and preimplant preparation. Vascular injury promotes intimal hyperplasia, the leading cause of graft failure, but the molecular events leading to this response are largely unknown. This study investigated adenosine triphosphate (ATP) as a potential molecular mediator in the vascular response to stretch injury, and the downstream effects of the purinergic receptor, P2X7R, and p38 MAPK activation.
MATERIALS AND METHODS - A subfailure stretch rat aorta model was used to determine the effect of stretch injury on release of ATP and vasomotor responses. Stretch-injured tissues were treated with apyrase, the P2X7R antagonist, A438079, or the p38 MAPK inhibitor, SB203580, and subsequent contractile forces were measured using a muscle bath. An exogenous ATP (eATP) injury model was developed and the experiment repeated. Change in p38 MAPK phosphorylation after stretch and eATP tissue injury was determined using Western blotting. Noninjured tissue was incubated in the p38 MAPK activator, anisomycin, and subsequent contractile function and p38 MAPK phosphorylation were analyzed.
RESULTS - Stretch injury was associated with release of ATP. Contractile function was decreased in tissue subjected to subfailure stretch, eATP, and anisomycin. Contractile function was restored by apyrase, P2X7R antagonism, and p38-MAPK inhibition. Stretch, eATP, and anisomycin-injured tissue demonstrated increased phosphorylation of p38 MAPK.
CONCLUSIONS - Taken together, these data suggest that the vascular response to stretch injury is associated with release of ATP and activation of the P2X7R/P38 MAPK pathway, resulting in contractile dysfunction. Modulation of this pathway in vein grafts after harvest and before implantation may reduce the vascular response to injury.
Copyright © 2017 Elsevier Inc. All rights reserved.
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Post-contractile BOLD contrast in skeletal muscle at 7 T reveals inter-individual heterogeneity in the physiological responses to muscle contraction.
Towse TF, Elder CP, Bush EC, Klockenkemper SW, Bullock JT, Dortch RD, Damon BM
(2016) NMR Biomed 29: 1720-1728
MeSH Terms: Adult, Blood Flow Velocity, Blood Volume, Female, Humans, Magnetic Resonance Imaging, Male, Muscle Contraction, Muscle, Skeletal, Oxygen, Oxygen Consumption, Physical Endurance, Reproducibility of Results, Sensitivity and Specificity
Show Abstract · Added October 24, 2018
Muscle blood oxygenation-level dependent (BOLD) contrast is greater in magnitude and potentially more influenced by extravascular BOLD mechanisms at 7 T than it is at lower field strengths. Muscle BOLD imaging of muscle contractions at 7 T could, therefore, provide greater or different contrast than at 3 T. The purpose of this study was to evaluate the feasibility of using BOLD imaging at 7 T to assess the physiological responses to in vivo muscle contractions. Thirteen subjects (four females) performed a series of isometric contractions of the calf muscles while being scanned in a Philips Achieva 7 T human imager. Following 2 s maximal isometric plantarflexion contractions, BOLD signal transients ranging from 0.3 to 7.0% of the pre-contraction signal intensity were observed in the soleus muscle. We observed considerable inter-subject variability in both the magnitude and time course of the muscle BOLD signal. A subset of subjects (n = 7) repeated the contraction protocol at two different repetition times (T : 1000 and 2500 ms) to determine the potential of T -related inflow effects on the magnitude of the post-contractile BOLD response. Consistent with previous reports, there was no difference in the magnitude of the responses for the two T values (3.8 ± 0.9 versus 4.0 ± 0.6% for T  = 1000 and 2500 ms, respectively; mean ± standard error). These results demonstrate that studies of the muscle BOLD responses to contractions are feasible at 7 T. Compared with studies at lower field strengths, post-contractile 7 T muscle BOLD contrast may afford greater insight into microvascular function and dysfunction.
Copyright © 2016 John Wiley & Sons, Ltd.
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Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction.
Gilliam LA, Lark DS, Reese LR, Torres MJ, Ryan TE, Lin CT, Cathey BL, Neufer PD
(2016) Am J Physiol Endocrinol Metab 311: E293-301
MeSH Terms: Animals, Antineoplastic Agents, Breast Neoplasms, Catalase, Disease Models, Animal, Doxorubicin, Electron Transport Complex I, Electron Transport Complex II, Female, Hydrogen Peroxide, Mice, Mice, Transgenic, Mitochondria, Muscle, Muscle Contraction, Muscle, Skeletal, Oxidation-Reduction, Proteins
Show Abstract · Added October 17, 2016
The loss of strength in combination with constant fatigue is a burden on cancer patients undergoing chemotherapy. Doxorubicin, a standard chemotherapy drug used in the clinic, causes skeletal muscle dysfunction and increases mitochondrial H2O2 We hypothesized that the combined effect of cancer and chemotherapy in an immunocompetent breast cancer mouse model (E0771) would compromise skeletal muscle mitochondrial respiratory function, leading to an increase in H2O2-emitting potential and impaired muscle function. Here, we demonstrate that cancer chemotherapy decreases mitochondrial respiratory capacity supported with complex I (pyruvate/glutamate/malate) and complex II (succinate) substrates. Mitochondrial H2O2-emitting potential was altered in skeletal muscle, and global protein oxidation was elevated with cancer chemotherapy. Muscle contractile function was impaired following exposure to cancer chemotherapy. Genetically engineering the overexpression of catalase in mitochondria of muscle attenuated mitochondrial H2O2 emission and protein oxidation, preserving mitochondrial and whole muscle function despite cancer chemotherapy. These findings suggest mitochondrial oxidants as a mediator of cancer chemotherapy-induced skeletal muscle dysfunction.
Copyright © 2016 the American Physiological Society.
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17 MeSH Terms
Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension.
West JD, Carrier EJ, Bloodworth NC, Schroer AK, Chen P, Ryzhova LM, Gladson S, Shay S, Hutcheson JD, Merryman WD
(2016) PLoS One 11: e0148657
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, Cell Movement, Cytoskeletal Proteins, Gene Expression Profiling, Gene Expression Regulation, Hypertension, Pulmonary, Indoles, Lung, Mice, Mice, Transgenic, Muscle Contraction, Muscle Proteins, Mutation, Myocytes, Smooth Muscle, Oligonucleotide Array Sequence Analysis, Phosphorylation, Protein Transport, Receptor, Serotonin, 5-HT2B, Serotonin Antagonists, Signal Transduction, Urea, Vascular Stiffness, src-Family Kinases
Show Abstract · Added April 11, 2017
Serotonergic anorexigens are the primary pharmacologic risk factor associated with pulmonary arterial hypertension (PAH), and the resulting PAH is clinically indistinguishable from the heritable form of disease, associated with BMPR2 mutations. Both BMPR2 mutation and agonists to the serotonin receptor HTR2B have been shown to cause activation of SRC tyrosine kinase; conversely, antagonists to HTR2B inhibit SRC trafficking and downstream function. To test the hypothesis that a HTR2B antagonist can prevent BMRP2 mutation induced PAH by restricting aberrant SRC trafficking and downstream activity, we exposed BMPR2 mutant mice, which spontaneously develop PAH, to a HTR2B antagonist, SB204741, to block the SRC activation caused by BMPR2 mutation. SB204741 prevented the development of PAH in BMPR2 mutant mice, reduced recruitment of inflammatory cells to their lungs, and reduced muscularization of their blood vessels. By atomic force microscopy, we determined that BMPR2 mutant mice normally had a doubling of vessel stiffness, which was substantially normalized by HTR2B inhibition. SB204741 reduced SRC phosphorylation and downstream activity in BMPR2 mutant mice. Gene expression arrays indicate that the primary changes were in cytoskeletal and muscle contractility genes. These results were confirmed by gel contraction assays showing that HTR2B inhibition nearly normalizes the 400% increase in gel contraction normally seen in BMPR2 mutant smooth muscle cells. Heritable PAH results from increased SRC activation, cellular contraction, and vascular resistance, but antagonism of HTR2B prevents SRC phosphorylation, downstream activity, and PAH in BMPR2 mutant mice.
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24 MeSH Terms
Comparative structural and functional analysis of the larval and adult dorsal vessel and its role in hemolymph circulation in the mosquito Anopheles gambiae.
League GP, Onuh OC, Hillyer JF
(2015) J Exp Biol 218: 370-80
MeSH Terms: Animals, Anopheles, Female, Heart, Hemolymph, Larva, Metamorphosis, Biological, Muscle Contraction, Video Recording
Show Abstract · Added February 5, 2016
Hemolymph circulation in insects is driven primarily by the contractile action of a dorsal vessel, which is divided into an abdominal heart and a thoracic aorta. As holometabolous insects, mosquitoes undergo striking morphological and physiological changes during metamorphosis. This study presents a comprehensive structural and functional analysis of the larval and adult dorsal vessel in the malaria mosquito Anopheles gambiae. Using intravital video imaging we show that, unlike the adult heart, the larval heart contracts exclusively in the anterograde direction and does not undergo heartbeat directional reversals. The larval heart contracts 24% slower than the adult heart, and hemolymph travels across the larval dorsal vessel at a velocity that is 68% slower than what is seen in adults. By fluorescently labeling muscle tissue we show that although the general structure of the heart and its ostia are similar across life stages, the heart-associated alary muscles are significantly less robust in larvae. Furthermore, unlike the adult ostia, which are the entry points for hemolymph into the heart, the larval ostia are almost entirely lacking in incurrent function. Instead, hemolymph enters the larval heart through incurrent openings located at the posterior terminus of the heart. These posterior openings are structurally similar across life stages, but in adults have an opposite, excurrent function. Finally, the larval aorta and heart differ significantly in the arrangement of their cardiomyocytes. In summary, this study provides an in-depth developmental comparison of the circulatory system of larval and adult mosquitoes.
© 2015. Published by The Company of Biologists Ltd.
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9 MeSH Terms
Slow wave conduction patterns in the stomach: from Waller's foundations to current challenges.
Cheng LK
(2015) Acta Physiol (Oxf) 213: 384-93
MeSH Terms: Animals, Arrhythmias, Cardiac, Cell Movement, Electromagnetic Phenomena, Humans, Models, Biological, Muscle Contraction, Stomach
Show Abstract · Added April 26, 2016
This review provides an overview of our understanding of motility and slow wave propagation in the stomach. It begins by reviewing seminal studies conducted by Walter Cannon and Augustus Waller on in vivo motility and slow wave patterns. Then our current understanding of slow wave patterns in common laboratory animals and humans is presented. The implications of slow wave arrhythmic patterns that have been recorded in animals and patients suffering from gastroparesis are discussed. Finally, current challenges in experimental methods and techniques, slow wave modulation and the use of mathematical models are discussed.
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
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8 MeSH Terms
Brilliant blue FCF as an alternative dye for saphenous vein graft marking: effect on conduit function.
Voskresensky IV, Wise ES, Hocking KM, Li FD, Osgood MJ, Komalavilas P, Brophy C, Cheung-Flynn J
(2014) JAMA Surg 149: 1176-81
MeSH Terms: Analysis of Variance, Animals, Benzenesulfonates, Coloring Agents, Endothelium, Vascular, Graft Survival, Humans, Muscle Contraction, Muscle, Smooth, Vascular, Organ Culture Techniques, Primary Graft Dysfunction, Rats, Rats, Sprague-Dawley, Saphenous Vein, Vena Cava, Inferior
Show Abstract · Added March 9, 2015
IMPORTANCE - Surgical skin markers are used off-label to mark human saphenous veins (HSVs) to maintain orientation before implantation as aortocoronary or peripheral arterial bypass grafts. These surgical skin markers impair functional responses of the HSV tissue.
OBJECTIVES - To investigate the effect of brilliant blue dye 1 (brilliant blue FCF [for food coloring]; hereinafter, FCF) as a nontoxic alternative marking dye and to determine whether FCF has pharmacological properties.
DESIGN, SETTING, AND PARTICIPANTS - Segments of HSVs were collected in university hospitals from patients undergoing coronary artery bypass grafting procedures immediately after harvest (unmanipulated) or after typical intraoperative surgical graft preparation (after manipulation). Rat inferior venae cavae were used to determine the pharmacological properties and cellular targets of FCF. Endothelial and smooth muscle functional responses were determined in a muscle bath, and intimal thickening in HSVs was determined after 14 days in organ culture.
MAIN OUTCOMES AND MEASURES - Contractile responses were measured in force and converted to stress. Smooth muscle function was expressed as maximal responses to potassium chloride depolarization contractions. Endothelial function was defined as the percentage of relaxation of maximal agonist-induced contraction. Neointimal thickness was measured by histomorphometric analysis.
RESULTS - Human saphenous veins stored in the presence of FCF had no loss of endothelial or smooth muscle function. Unmanipulated HSVs preserved in the presence of FCF demonstrated a significant increase in endothelial-dependent relaxation (mean [SEM], 25.2% [6.4%] vs 30.2% [6.7%]; P = .02). Application of FCF to functionally nonviable tissue significantly enhanced the smooth muscle responses (mean [SEM], 0.018 [0.004] × 10⁵ N/m² vs 0.057 [0.016] × 10⁵ N/m²; P = .05). Treatment with FCF reduced intimal thickness in organ culture (mean [SEM], -17.5% [2.1%] for unmanipulated HSVs vs -27.9% [3.7%] for HSVs after manipulation; P < .001). In rat inferior venae cavae, FCF inhibited the contraction induced by the P2X7 receptor agonist 2'(3')-O-(4-benzoyl)benzoyl-adenosine-5'-triphosphate (mean [SEM], 14.8% [2.2%] vs 6.5% [1.8%]; P = .02) to an extent similar to the P2X7 receptor antagonist oxidized adenosine triphosphate (mean [SEM], 5.0% [0.9%]; P < .02 vs control) or the pannexin hemichannel inhibitor probenecid (mean [SEM], 7.3% [1.6%] and 4.7% [0.9%] for 0.5mM and 2mM, respectively; P < .05).
CONCLUSIONS AND RELEVANCE - Treatment with FCF did not impair endothelial or smooth muscle function in HSVs. Brilliant blue FCF enhanced endothelial-dependent relaxation, restored smooth muscle function, and prevented intimal hyperplasia in HSVs in organ culture. These pharmacological properties of FCF may be due to P2X7 receptor or pannexin channel inhibition. Brilliant blue FCF is an alternative, nontoxic marking dye that may improve HSV conduit function and decrease intimal hyperplasia.
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15 MeSH Terms
A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: comparison with effects of contraction and other AMPK activators.
Lai YC, Kviklyte S, Vertommen D, Lantier L, Foretz M, Viollet B, Hallén S, Rider MH
(2014) Biochem J 460: 363-75
MeSH Terms: AMP-Activated Protein Kinases, Acetyl-CoA Carboxylase, Aminoimidazole Carboxamide, Animals, Benzimidazoles, Enzyme Activation, Fatty Acids, Glucose, Glycogen, Male, Mice, Muscle Contraction, Muscle, Skeletal, Pyrones, Rats, Ribonucleotides, Thiophenes
Show Abstract · Added August 18, 2014
AMPK (AMP-activated protein kinase) is an attractive therapeutic drug target for treating metabolic disorders. We studied the effects of an AMPK activator developed by Merck (ex229 from patent application WO2010036613), comparing chemical activation with contraction in intact incubated skeletal muscles. We also compared effects of ex229 with those of the Abbott A769662 compound and AICAR (5-amino-4-imidazolecarboxamide riboside). In rat epitrochlearis muscle, ex229 dose-dependently increased AMPK activity of α1-, α2-, β1- and β2-containing complexes with significant increases in AMPK activity seen at a concentration of 50 μM. At a concentration of 100 μM, AMPK activation was similar to that observed after contraction and importantly led to an ~2-fold increase in glucose uptake. In AMPK α1-/α2-catalytic subunit double-knockout myotubes incubated with ex229, the increases in glucose uptake and ACC (acetyl-CoA carboxylase) phosphorylation seen in control cells were completely abolished, suggesting that the effects of the compound were AMPK-dependent. When muscle glycogen levels were reduced by ~50% after starvation, ex229-induced AMPK activation and glucose uptake were amplified in a wortmannin-independent manner. In L6 myotubes incubated with ex229, fatty acid oxidation was increased. Furthermore, in mouse EDL (extensor digitorum longus) and soleus muscles, ex229 increased both AMPK activity and glucose uptake at least 2-fold. In summary, ex229 efficiently activated skeletal muscle AMPK and elicited metabolic effects in muscle appropriate for treating Type 2 diabetes by stimulating glucose uptake and increasing fatty acid oxidation.
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17 MeSH Terms
AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity.
Lantier L, Fentz J, Mounier R, Leclerc J, Treebak JT, Pehmøller C, Sanz N, Sakakibara I, Saint-Amand E, Rimbaud S, Maire P, Marette A, Ventura-Clapier R, Ferry A, Wojtaszewski JF, Foretz M, Viollet B
(2014) FASEB J 28: 3211-24
MeSH Terms: AMP-Activated Protein Kinases, Animals, Glucose, Interleukin-6, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Muscle Contraction, Muscle Fatigue, Muscle Fibers, Skeletal, Oxidation-Reduction, Phosphorylation, Physical Conditioning, Animal, Physical Endurance
Show Abstract · Added April 17, 2014
AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a central role in skeletal muscle metabolism. We used skeletal muscle-specific AMPKα1α2 double-knockout (mdKO) mice to provide direct genetic evidence of the physiological importance of AMPK in regulating muscle exercise capacity, mitochondrial function, and contraction-stimulated glucose uptake. Exercise performance was significantly reduced in the mdKO mice, with a reduction in maximal force production and fatigue resistance. An increase in the proportion of myofibers with centralized nuclei was noted, as well as an elevated expression of interleukin 6 (IL-6) mRNA, possibly consistent with mild skeletal muscle injury. Notably, we found that AMPKα1 and AMPKα2 isoforms are dispensable for contraction-induced skeletal muscle glucose transport, except for male soleus muscle. However, the lack of skeletal muscle AMPK diminished maximal ADP-stimulated mitochondrial respiration, showing an impairment at complex I. This effect was not accompanied by changes in mitochondrial number, indicating that AMPK regulates muscle metabolic adaptation through the regulation of muscle mitochondrial oxidative capacity and mitochondrial substrate utilization but not baseline mitochondrial muscle content. Together, these results demonstrate that skeletal muscle AMPK has an unexpected role in the regulation of mitochondrial oxidative phosphorylation that contributes to the energy demands of the exercising muscle.-Lantier, L., Fentz, J., Mounier, R., Leclerc, J., Treebak, J. T., Pehmøller, C., Sanz, N., Sakakibara, I., Saint-Amand, E., Rimbaud, S., Maire, P., Marette, A., Ventura-Clapier, R., Ferry, A., Wojtaszewski, J. F. P., Foretz, M., Viollet, B. AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity.
© FASEB.
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16 MeSH Terms