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At least 703 records · Page 39
All sourcesNASA NTRSDOE OSTI
DOE OSTI2012

Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy

Calcium channel blockers (CCBs) are important in the management of hypertension and limit restenosis. Although CCB efficacy could derive from decreased blood pressure, other mechanisms independent of CCB activity also can contribute to antiproliferative action. To understand mechanisms of CCB-mediated antiproliferation, we studied two structurally dissimilar CCBs, diltiazem and verapamil, in cultured rat vascular smooth muscle cells (VSMC). To elucidate CCB-independent effects, pure stereoisomers of verapamil (R-verapamil, inactive VR; S-verapamil, active, VS) were used. The effects of CCB exposure on cell viability (MTT reduction), cell proliferation ({sup 3}H-thymidine incorporation), VSMC morphology by light and transmission electron microscopy (TEM) and autophagy (LC3I/II, ATG5) were measured. In general, verapamil, VR or VS treatment alone (80 μM) appreciably enhanced MTT absorbance although higher concentrations (VR or VS) slightly decreased MTT absorbance. Diltiazem (140 μM) markedly decreased MTT absorbance (40%) at 120 h. VR or VS treatment inhibited {sup 3}H-thymidine incorporation (24 h) and induced cytological alterations (i.e., karyokinesis, enhanced perinuclear MTT deposition, accumulated perinuclear “vacuoles”). TEM revealed perinuclear “vacuoles” to be aggregates of highly laminated and electron-dense vesicles resembling autophagosomes and lysosomes, respectively. Increased autophagosome activity was confirmed by a concentration-dependent increase in LC3-II formation by Western blotting and by increased perinuclear LC3-GFP{sup +} puncta in verapamil-treated VSMC. Verapamil stereoisomers appeared to decrease perinuclear mitochondrial density. These observations indicate that antiproliferative effects of verapamil stereoisomers are produced by enhanced mitochondrial damage and upregulated autophagy in VSMC. These effects are independent of CCB activity indicating a distinct mechanism of action that could be targeted for more efficacious anti-atherosclerotic and anti-restenosis therapy. Highlights: ► Calcium channel blockers (CCB) are antiproliferative in vascular smooth muscle cells. ► Verapamil stereoisomers are antiproliferative in VSMC independent of CCB activity. ► Verapamil stereoisomers alter mitochondrial appearance and frequency in VSMC. ► Verapamil stimulates autophagy in cultured VSMC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Effects of acute ethanol exposure on cytokine production by primary airway smooth muscle cells

Both chronic and binge alcohol abuse can be significant risk factors for inflammatory lung diseases such as acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, metabolic basis of alcohol-related lung disease is not well defined, and may include key metabolites of ethanol [EtOH] in addition to EtOH itself. Therefore, we investigated the effects of EtOH, acetaldehyde [ACE], and fatty acid ethyl esters [FAEEs] on oxidative stress, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and nuclear translocation of phosphorylated (p)-NF-κB p65 in primary human airway smooth muscle (HASM) cells stimulated to produce cytokines using LPS exposure. Both FAEEs and ACE induced evidence of cellular oxidative stress and ER stress, and increased p-NF-κB in nuclear extracts. EtOH and its metabolites decreased p-AMPKα activation, and induced expression of fatty acid synthase, and decreased expression of sirtuin 1. In general, EtOH decreased secretion of IP-10, IL-6, eotaxin, GCSF, and MCP-1. However, FAEEs and ACE increased these cytokines, suggesting that both FAEEs and ACE as compared to EtOH itself are proinflammatory. A direct effect of EtOH could be consistent with blunted immune response. Collectively, these two features of EtOH exposure, coupled with the known inhibition of innate immune response in our model might explain some clinical manifestations of EtOH exposure in the lung. - Highlights: • Metabolic basis for EtOH toxicity was studied in human airway smooth muscle (HASM) cells. • In HASM cells, EtOH metabolites were found to be relatively more toxic than EtOH itself. • EtOH metabolites mediate deactivation of AMPK via oxidative stress and ER stress. • EtOH metabolites were found to be more proinflammatory than EtOH itself in HASM cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a familiar fatal progressive degenerative disorder characterized by cognitive decline, and recurrent stroke in young adults. Pathological features include a dramatic reduction of brain vascular smooth muscle cells and severe arteriopathy with the presence of granular osmophilic material in the arterial walls. Here we have investigated the cellular and mitochondrial function in vascular smooth muscle cell lines (VSMCs) established from CADASIL mutation carriers (R133C) and healthy controls. We found significantly lower proliferation rates in CADASIL VSMC as compared to VSMC from controls. Cultured CADASIL VSMCs were not more vulnerable than control cells to a number of toxic substances. Morphological studies showed reduced mitochondrial connectivity and increased number of mitochondria in CADASIL VSMCs. Transmission electron microscopy analysis demonstrated increased irregular and abnormal mitochondria in CADASIL VSMCs. Measurements of mitochondrial membrane potential (Δψ{sub m}) showed a lower percentage of fully functional mitochondria in CADASIL VSMCs. For a number of genes previously reported to be changed in CADASIL VSMCs, immunoblotting analysis demonstrated a significantly reduced SOD1 expression. These findings suggest that alteration of proliferation and mitochondrial function in CADASIL VSMCs might have an effect on vital cellular functions important for CADASIL pathology. -- Highlights: ► CADASIL is an inherited disease of cerebral vascular cells. ► Mitochondrial dysfunction has been implicated in the pathogenesis of CADASIL. ► Lower proliferation rates in CADASIL VSMC. ► Increased irregular and abnormal mitochondria and lower mitochondrial membrane potential in CADASIL VSMCs. ► Reduced mitochondrial connectivity and increased number of mitochondria in CADASIL VSMCs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Roxithromycin inhibits VEGF-induced human airway smooth muscle cell proliferation: Opportunities for the treatment of asthma

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferation and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma. - Highlights: • RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. • VEGF-induced cell proliferation was suppressed by inhibiting the activity of ERK1/2. • RXM inhibits activation of VEGFR2 and ERK and downregulation of caveolin-1. • RXM inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. • Our findings expand our knowledge of the role of RXM in airway remodelling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Msx1-modulated muscle satellite cells retain a primitive state and exhibit an enhanced capacity for osteogenic differentiation

Multipotent muscle satellite cells (MuSCs) have been identified as potential seed cells for bone tissue engineering. However, MuSCs exhibit a rapid loss of stemness after in vitro culturing, thereby compromising their therapeutic efficiency. Muscle segment homeobox gene 1 (msx1) has been found to induce the dedifferentiation of committed progenitor cells, as well as terminally differentiated myotubes. In this study, a Tet-off retroviral gene delivery system was used to modulate msx1 expression. After ten passages, MuSCs that did not express msx-1 (e.g., the non-msx1 group) were compared with MuSCs with induced msx-1 expression (e.g., the msx1 group). The latter group exhibited a more juvenile morphology, it contained a significantly lower percentage of senescent cells characterized by positive β-galactosidase staining, and it exhibited increased proliferation and a higher proliferation index. Immunocytochemical stainings further detected a more primitive gene expression profile for the msx1 group, while osteogenic differentiation assays and ectopic bone formation assays demonstrated an improved capacity for the msx1 group to undergo osteogenic differentiation. These results suggest that transient expression of msx1 in MuSCs can retain a primitive state, thereby enhancing their capacity for osteogenic differentiation and restoring the potential for MuSCs to serve as seed cells for bone tissue engineering.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Plasminogen activator Inhibitor-2 inhibits pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension via PI3K/Akt and ERK signaling

Highlights: • Serum PAI-2 is decreased in patients with pulmonary arterial hypertension. • Serum PAI-2 is associated with disease severity in pulmonary arterial hypertension. • Exogenous PAI-2 attenuates monocrotaline induced pulmonary hypertension in rats. • PAI-2 inhibits pulmonary arterial smooth muscle proliferation via PI3K/Akt and ERK. The proliferation of pulmonary arterial smooth muscle cells (PASMCs) and subsequent pulmonary vascular remodeling leads to pulmonary arterial hypertension (PAH). Understanding the underlying mechanisms and identifying molecules that can suppress PASMCs proliferation is critical for developing effective pharmacological treatment. We previously showed that plasminogen activator inhibitor-2 (PAI-2) inhibited human PASMC (hPASMCs) proliferation in vitro. However, its inhibitory effect on PAH remains to be determined, and the mechanism remains to be illustrated.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

N6-methyladenine demethylase ALKBH1 inhibits the differentiation of skeletal muscle

Highlights: • The DNA N6-mA modification increased during skeletal muscle development, accompanied by a strong decrease of ALKBH1. • ALKBH1 enhanced proliferation and inhibited differentiation of C2C12 cells. • ALKBH1 impaired multiple genes and signaling pathways to promote proliferation and inhibit differentiation of C2C12 cells. DNA N{sup 6}-methyladenine (N6-mA) was recently recognized as a new epigenetic modification in mammalian genome, and ALKBH1 was discovered as its demethylase. Knock-out mice studies revealed that ALKBH1 was indispensable for normal embryonic development. However, the function of ALKBH1 in myogenesis is largely unknown. In this study, we found that N6-mA showed a steady increase, going along with a strong decrease of ALKBH1 during skeletal muscle development. Our results also showed that ALKBH1 enhanced proliferation and inhibited differentiation of C2C12 cells. Genome-wide transcriptome analysis and reporter assays further revealed that ALKBH1 accomplished the differentiation inhibiting function by regulating a core set of genes and multiple signaling pathways, including increasing chemokine (C-X-C motif) ligand 14 (CXCL14) and activating ERK signaling. Taken together, our results demonstrated that ALKBH1 is critical for the myogenic differentiation of C2C12 cells, and suggested that N6-mA might be a new epigenetic mechanism for the regulation of myogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Micro- and nanostructured electro-active polymer actuators as smart muscles for incontinence treatment

Treatments of severe incontinence are currently based on purely mechanical systems that generally result in revision after three to five years. Our goal is to develop a prototype acting in a natural-analogue manner as artificial muscle, which is based on electro-active polymers. Dielectric actuators have outstanding performances including millisecond response times, mechanical strains of more than 10 % and power to mass densities similar to natural muscles. They basically consist of polymer films sandwiched between two compliant electrodes. The incompressible but elastic polymer film transduces the electrical energy into mechanical work according to the Maxwell pressure. Available polymer films are micrometers thick and voltages as large as kV are necessary to obtain 10 % strain. For medical implants, polymer films should be nanometer thin to realize actuation below 48 V. The metallic electrodes have to be stretchable to follow the strain of 10 % and remain conductive. Recent results on the stress/strain behavior of anisotropic EAP-cantilevers have shown dependencies on metal electrode preparation. We have investigated tunable anisotropic micro- and nanostructures for metallic electrodes. They show a preferred actuation direction with improved stress-strain behavior. The bending of the cantilever has been characterized by the laser beam deflection method. The impact of the electrode on the effective Young's Modulus is measured using an Ultra Nanoindentation Tester with an integrated reference system for soft polymer surfaces. Once ten thousand layers of nanometer-thin EAP actuators are available, devices beyond the envisioned application will flood the market.

36 MATERIALS SCIENCE↗
DOE OSTI2012

Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction

The myosin essential light chain (ELC) is a structural component of the actomyosin cross-bridge, but its function is poorly understood, especially the role of the cardiac specific N-terminal extension in modulating actomyosin interaction. Here, we generated transgenic (Tg) mice expressing the A57G (alanine to glycine) mutation in the cardiac ELC known to cause familial hypertrophic cardiomyopathy (FHC). The function of the ELC N-terminal extension was investigated with the Tg-{Delta}43 mouse model, whose myocardium expresses a truncated ELC. Low-angle X-ray diffraction studies on papillary muscle fibers in rigor revealed a decreased interfilament spacing ({approx} 1.5 nm) and no alterations in cross-bridge mass distribution in Tg-A57G mice compared to Tg-WT, expressing the full-length nonmutated ELC. The truncation mutation showed a 1.3-fold increase in I{sub 1,1}/I{sub 1,0}, indicating a shift of cross-bridge mass from the thick filament backbone toward the thin filaments. Mechanical studies demonstrated increased stiffness in Tg-A57G muscle fibers compared to Tg-WT or Tg-{Delta}43. The equilibrium constant for the cross-bridge force generation step was smallest in Tg-{Delta}43. These results support an important role for the N-terminal ELC extension in prepositioning the cross-bridge for optimal force production. Subtle changes in the ELC sequence were sufficient to alter cross-bridge properties and lead to pathological phenotypes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Theoretical Control-Centric Modeling for Precision Model-Based Sliding Mode Control of a Hydraulic Artificial Muscle Actuator

Artificial muscles (AMs) typically rely on pneumatic sources of fluid power. The use of hydraulics can increase the power and force to weight and volume ratios of AM actuators. This paper develops a control-centric third-order single-input single-output (SISO) lumped-parameter dynamic model and sliding mode position controller based on Filippov's principle of equivalent dynamics for a braided hydraulic artificial muscle (HAM) actuator. The model predicts the nonlinear behavior of the HAM free contraction and captures the fluid and actuator nonlinear dynamic interactions in addition to the braid deformation. Model simulations are compared to experimental results for quasi-static pressurization, isometric pressurization, and open-loop square wave commands at 0.25, 0.5, and 1 Hz. Experiments of sine wave tracking at 0.25, 0.5, and 1 Hz and continuous square wave tracking at 0.067 Hz are conducted using a sliding mode controller (SMC) derived from the model. The SMC achieves a steady-state error of 6 μm at multiple setpoints within the actuator's 17 mm stroke. Compared to a proportional-integral-derivative (PID) controller, the SMC root-mean-square (RMS) error, mean error, and absolute maximum error are reduced on average by 53%, 61%, and 44%, respectively, demonstrating the benefit of model-based approaches for controlling HAMs.

42 ENGINEERING↗
DOE OSTI2014

Temperature elevation by HIFU in ex vivo porcine muscle: MRI measurement and simulation study

Purpose: High-intensity focused ultrasound is a rapidly developing medical technology with a large number of potential clinical applications. Computational model can play a pivotal role in the planning and optimization of the treatment based on the patient's image. Nonlinear propagation effects can significantly affect the temperature elevation and should be taken into account. In order to investigate the importance of nonlinear propagation effects, nonlinear Westervelt equation was solved. Weak nonlinear propagation effects were studied. The purpose of this study was to investigate the correlation between the predicted and measured temperature elevations and lesion in a porcine muscle. Methods: The investigated single-element transducer has a focal length of 12 cm, an aperture of 8 cm, and frequency of 1.08 MHz. Porcine muscle was heated for 30 s by focused ultrasound transducer with an acoustic power in the range of 24–56 W. The theoretical model consists of nonlinear Westervelt equation with relaxation effects being taken into account and Pennes bioheat equation. Results: Excellent agreement between the measured and simulated temperature rises was found. For peak temperatures above 85–90 °C “preboiling” or cavitation activity appears and lesion distortion starts, causing small discrepancy between the measured and simulated temperature rises. From the measurements and simulations, it was shown that distortion of the lesion was caused by the “preboiling” activity. Conclusions: The present study demonstrated that for peak temperatures below 85–90 °C numerical simulation results are in excellent agreement with the experimental data in three dimensions. Both temperature rise and lesion size can be well predicted. Due to nonlinear effect the temperature in the focal region can be increased compared with the linear case. The current magnetic resonance imaging (MRI) resolution is not sufficient. Due to the inevitable averaging the measured temperature can be 10–30 °C lower than the peak temperature. Computational fluid dynamics can provide additional important information that is lost using a state of the art MRI device.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

TU-C-12A-01: Measurement of Skeletal Muscle Lipids in Type 2 Diabetes Using in Vivo Proton MR Spectroscopy

Purpose: To quantify and compare the intramyocellular (IMCL), extramyocellular (EMCL) lipids and total fat fraction in human vastus lateralis (VL) muscle between lean controls and type 2 diabetic (T2DM) subjects using long echo time in vivo proton MR spectroscopy ({sup 1}H-MRS) Methods: {sup 1}H-MRS single voxel (15 × 15 × 15 mm{sup 3}) stimulated acquisition mode (STEAM) was performed in right vastus lateralis m. on 10 lean controls (age: 28.3±3.94 yrs, BMI: 24.25±3.20 kg/m{sup 2}) and 7 type 2 diabetic (age: 54.28±6.42 yrs, BMI: 31.34±3.13 kg/m{sup 2}) subjects with Siemens 3T MRI and four-channel flex coil. Unsuppressed water spectra (NSA = 16) with TR/TE = 3000/30 msec, TM = 10 msec, BW = 2000 Hz, and water-suppressed spectra (NSA = 128) with TR/TE = 3000/270 msec, TM = 10 msec, and fixed water suppression BW = 50 Hz were acquired. Spectral intensity ratios of IMCL-CH{sub 2}, EMCL-CH{sub 2} and total lipid (IMCL {sub +} EMCL) with unsuppressed water signal (W) were converted into absolute concentrations expressed in mmol/kg. Fat fraction (100 × F/(W+F)) was calculated, where F includes the signal intensities of IMCL and EMCL methylene (CH{sub 2})n, peaks only. Results: Comparison of IMCL (controls: 11.70 ± 6.7, T2DM: 21.74 ± 10.2, p ≤ 0.01), EMCL (controls: 22.89 ± 18.42, T2DM: 77.21 ± 33.4, p ≤ 0.001) and total lipid (64.35 mmol/kg less in controls, p ≤ 0.001) showed statistical significance using two-tailed student t-test. Fat fraction (%) exhibited considerable inter-individual variability for controls (3.14 ± 2.09; range: 1.34 - 7.04) and T2DM (9.34 ± 2.88; range: 4.15 - 13.67) and deemed significant (p ≤ 0.05 Conclusion: Single voxel STEAM {sup 1}H-MRS at long TE provides a robust non-invasive method for characterizing lipids within localized muscle regions, with well-resolved IMCL/EMCL peak separation. Regional lipid estimate and fat fraction in VL m. was significantly different in T2DM compared to lean controls. American Heart Association Southwest Affiliate Pre-doctoral Fellowship.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Association Between Preoperative Muscle Mass and Intraoperative Bacterial Translocation in Patients Undergoing Hepatectomy, Pancreatoduodenectomy, and Esophagectomy

Purpose: This study investigated the correlation between the fecal profile and muscle mass, which has not been elucidated before. Methods: This study included patients who underwent hepatectomy, pancreatoduodenectomy, or esophagectomy and had fecal samples collected preoperatively and mesenteric lymph nodes (MLNs) harvested intraoperatively to determine the fecal profile and presence of bacteria in the MLNs. Total psoas area (TPA) was measured at the third lumbar vertebra using preoperative computed tomography images. TPA was standardized by body surface area (BSA) using the following equation: standardized TPA (mm{sup 2}/m{sup 2}) (stTPA) = TPA (mm{sup 2})/BSA (m{sup 2}). The fecal concentrations of representative microorganisms and organic acids also were measured. Results: A total of 127 patients undergoing hepatectomy (n = 48), pancreatoduodenectomy (n = 44), and esophagectomy (n = 35) were included. The fecal levels of predominant obligate anaerobes showed a positive correlation with stTPA, whereas that of pathogenic microorganisms showed a negative correlation with stTPA. The fecal concentrations of total short chain fatty acids (the sum of acetic acid, propionic acid, and butyric acid) also showed a positive correlation with stTPA. The stTPA was significantly lower in patients with positive microorganisms in the MLNs (patients with bacterial translocation) compared to those without microorganisms in the MLNs (p = 0.047). Conclusions: This study was the first to demonstrate the association between muscle mass and the fecal profile, as well as their association with bacterial translocation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
NASA NTRS2003

Noninvasive, near infrared spectroscopic-measured muscle pH and PO2 indicate tissue perfusion for cardiac surgical patients undergoing cardiopulmonary bypass

OBJECTIVE: To determine whether near infrared spectroscopic measurement of tissue pH and Po2 has sufficient accuracy to assess variation in tissue perfusion resulting from changes in blood pressure and metabolic demand during cardiopulmonary bypass. DESIGN: Prospective clinical study. SETTING: Academic medical center. SUBJECTS: Eighteen elective cardiac surgical patients. INTERVENTION: Cardiac surgery under cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: A near infrared spectroscopic fiber optic probe was placed over the hypothenar eminence. Reference Po2 and pH sensors were inserted in the abductor digiti minimi (V). Data were collected every 30 secs during surgery and for 6 hrs following cardiopulmonary bypass. Calibration equations developed from one third of the data were used with the remaining data to investigate sensitivity of the near infrared spectroscopic measurement to physiologic changes resulting from cardiopulmonary bypass. Near infrared spectroscopic and reference pH and Po2 measurements were compared for each subject using standard error of prediction. Near infrared spectroscopic pH and Po2 at baseline were compared with values during cardiopulmonary bypass just before rewarming commenced (hypotensive, hypothermic), after rewarming (hypotensive, normothermic) just before discontinuation of cardiopulmonary bypass, and at 6 hrs following cardiopulmonary bypass (normotensive, normothermic) using mixed-model analysis of variance. Near infrared spectroscopic pH and Po2 were well correlated with the invasive measurement of pH (R2 =.84) and Po2 (R 2 =.66) with an average standard error of prediction of 0.022 +/- 0.008 pH units and 6 +/- 3 mm Hg, respectively. The average difference between the invasive and near infrared spectroscopic measurement was near zero for both the pH and Po2 measurements. Near infrared spectroscopic Po2 significantly decreased 50% on initiation of cardiopulmonary bypass and remained depressed throughout the bypass and monitored intensive care period. Near infrared spectroscopic pH decreased significantly during cardiopulmonary bypass, decreased significantly during rewarming, and remained depressed 6 hrs after cardiopulmonary bypass. Diabetic patients responded differently than nondiabetic subjects to cardiopulmonary bypass, with lower muscle pH values (p =.02). CONCLUSIONS: Near infrared spectroscopic-measured muscle pH and Po2 are sensitive to changes in tissue perfusion during cardiopulmonary bypass.

Non-NASA Center↗
NASA NTRS2001

Receptor-based differences in human aortic smooth muscle cell membrane stiffness

Cells respond to mechanical stimuli with diverse molecular responses. The nature of the sensory mechanism involved in mechanotransduction is not known, but integrins may play an important role. The integrins are linked to both the cytoskeleton and extracellular matrix, suggesting that probing cells via integrins should yield different mechanical properties than probing cells via non-cytoskeleton-associated receptors. To test the hypothesis that the mechanical properties of a cell are dependent on the receptor on which the stress is applied, human aortic smooth muscle cells were plated, and magnetic beads, targeted either to the integrins via fibronectin or to the transferrin receptor by use of an IgG antibody, were attached to the cell surface. The resistance of the cell to deformation ("stiffness") was estimated by oscillating the magnetic beads at 1 Hz by use of single-pole magnetic tweezers at 2 different magnitudes. The ratio of bead displacements at different magnitudes was used to explore the mechanical properties of the cells. Cells stressed via the integrins required approximately 10-fold more force to obtain the same bead displacements as the cells stressed via the transferrin receptors. Cells stressed via integrins showed stiffening behavior as the force was increased, whereas this stiffening was significantly less for cells stressed via the transferrin receptor (P<0.001). Mechanical characteristics of vascular smooth muscle cells depend on the receptor by which the stress is applied, with integrin-based linkages demonstrating cell-stiffening behavior.

Non-NASA Center↗
NASA NTRS1997

Intracellular pH changes in human aortic smooth muscle cells in response to fluid shear stress

The smooth muscle cell (SMC) layers of human arteries may be exposed to blood flow after endothelium denudation, for example, following balloon angioplasty treatment. These SMCs are also constantly subjected to pressure driven transmural fluid flow. Flow-induced shear stress can alter SMC growth and metabolism. Signal transduction mechanisms involved in these flow effects on SMCs are still poorly understood. In this work, the hypothesis that shear stress alters the intracellular pH (pHi) of SMC is examined. When exposed to venous and arterial levels of shear stress, human aortic smooth muscle cells (hASMC) undergo alkalinization. The alkalinization plateau persisted even after 20 min of cell exposure to flow. Addition of amiloride (10 micromoles) or its 5-(N-ethyl-N-isopropyl) analog (EIPA, 10 micromoles), both Na+/H+ exchanger inhibitors, attenuated intracellular alkalinization, suggesting the involvement of the Na+/H+ exchanger in this response. The same concentrations of these inhibitors did not show an effect on pHi of hASMCs in static culture. 4-Acetamido-4'-isothio-cyanatostilbene-2,2'-disulfonic acid (SITS, 1 mM), a Cl-/HCO3- exchange inhibitor, affected the pHi of hASMCs both in static and flow conditions. Our results suggest that flow may perturb the Na+/H+ exchanger leading to an alkalinization of hASMCs, a different response from the flow-induced acidification seen with endothelial cells at the same levels of shear stress. Understanding the flow-induced signal transduction pathways in the vascular cells is of great importance in the tissue engineering of vascular grafts. In the case of SMCs, the involvement of pHi changes in nitric oxide production and proliferation regulation highlights further the significance of such studies.

NASA Discipline Cell Biology↗
NASA NTRS2000

Rhesus leg muscle EMG activity during a foot pedal pressing task on Bion 11

Rhesus monkeys (Macaca mulatta) were trained to perform a foot lever pressing task for a food reward. EMG activity was recorded from selected lower limb muscles of 2 animals before, during, and after a 14-day spaceflight and from 3 animals during a ground-based simulation of the flight. Integrated EMG activity was calculated for each muscle during the 20-min test. Comparisons were made between data recorded before any experimental manipulations and during flight or flight simulation. Spaceflight reduced soleus (Sol) activity to 25% of preflight levels, whereas it was reduced to 50% of control in the flight simulation. During flight, medial gastrocnemius (MG) activity was reduced to 25% of preflight activity, whereas the simulation group showed normal activity levels throughout all tests. The change in MG activity was apparent in the first inflight recording, suggesting that some effect of microgravity on MG activity was immediate.

Flight Experiment↗
NASA NTRS2000

Fingertip contact suppresses the destabilizing influence of leg muscle vibration

Touch of the hand with a stationary surface at nonmechanically supportive force levels (<1 N) greatly attenuates postural sway during quiet stance. We predicted such haptic contact would also suppress the postural destabilization caused by vibrating the right peroneus brevis and longus muscles of subjects standing heel-to-toe with eyes closed. In experiment 1, ten subjects were tested under four conditions: no-vibration, no-touch; no-vibration, touch; vibration, no-touch; and vibration, touch. A hand-held physiotherapy vibrator (120 Hz) was applied approximately 5 cm above the malleolous to stimulate the peroneus longus and brevis tendons. Touch conditions involved contact of the right index finger with a laterally positioned surface (<1 N of force) at waist height. Vibration in the absence of finger contact greatly increased the mean sway amplitude of the center of pressure and of the head relative to the no-vibration, no-touch control condition (P < 0.001). The touch, no-vibration and touch-vibration conditions were not significantly different (P > 0.05) from each other and both had significantly less mean sway amplitude of head and of center of pressure than the other conditions (P < 0.01). In experiment 2, eight subjects stood heel-to-toe under touch and no-touch conditions involving 40-s duration trials of peroneus tendon vibration at different duty cycles: 1-, 2-, 3-, and 4-s ON and OFF periods. The vibrator was attached to the subject's leg and remotely activated. In the no-touch conditions, subjects showed periodic postural disruptions contingent on the duty cycle and mirror image rebounds with the offset of vibration. In the touch conditions, subjects were much less disrupted and showed compensations occurring within 500 ms of vibration onset and mirror image rebounds with vibration offset. Subjects were able to suppress almost completely the destabilizing influence of the vibration in the 3- and 4-s duty cycle trials. These experiments show that haptic contact of the hand with a stable surface can suppress abnormal proprioceptive and motor signals in leg muscles.

NASA Discipline Neuroscience↗