Relationship between force and regulatory myosin light chain phosphorylation in airway smooth muscle

Kai, Tetsuya; Yoshimura, Hayashi; Jones, Keith A.; Warner, David O.

doi:10.1152/ajplung.2000.279.1.l52

Cited by 16 publications

(20 citation statements)

References 35 publications

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“…Shown in Table 7 The fraction of phosphorylated MLC (f P ) at rest is predicted as 13.5 and 13.0% in cases 1 and 2, respectively. These values are in good agreement with experimental data: in canine tracheal smooth muscle, f p was found to range between 15 and 20% (31,46), and in smooth muscle strips from rabbit femoral arteries f p values were on the order of 10% (34).…”

Section: Model Validationsupporting

confidence: 89%

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Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta

Edwards

Cao

Pallone

2011

American Journal of Physiology-Renal Physiology

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signaling and MLC phosphorylation. At concentrations above 1 nM, O 2 Ϫ is predicted to modulate [Cacyt] and MCLP activity mostly by reducing NO bioavailability. The DVR vasoconstriction that is induced by high concentrations of H 2O2 can be explained by H2O2-mediated downregulation of MLCP and SERCA activity. We conclude that intrinsic generation of NO by the DVR wall may be sufficient to inhibit vasoconstriction by maintaining suppression of MLC phosphorylation. calcium signaling; hydrogen peroxide; superoxide; vascular smooth muscle NITRIC OXIDE (NO) acts as a local vasodilator in the renal medulla and plays an important role in the maintenance of medullary perfusion, medullary oxygenation, and blood pressure. Chronic inhibition of nitric oxide synthase (NOS) reduces medullary blood flow (MBF) and is associated with sodium retention and the development of hypertension (8, 41). Whereas NO increases MBF by promoting the vasodilation of descending vasa recta (DVR) or juxtamedullary arterioles, superoxide (O 2 Ϫ ) and hydrogen peroxide (H 2 O 2 ) act to reduce MBF by mechanisms that remain to be fully elucidated (17,37). In addition, NO inhibits, whereas O 2 Ϫ enhances, thick ascending limb sodium reabsorption (23). Hence, interactions between NO and O 2 Ϫ likely contribute to the long-term control of blood pressure; when the balance between these two radicals is shifted in favor of O 2 Ϫ (such as in diabetes and atherosclerosis, conditions that promote oxidative stress), renal vasoconstriction and tubular reabsorption increase, favoring hypertension (17).In a recent microperfusion study of DVR (4), we showed that intrinsic production of NO and reactive oxygen species (ROS) affects DVR vasoactivity. To elucidate the cellular pathways by which NO, O 2 Ϫ , and H 2 O 2 modulate DVR contraction, in the present study we expanded our mathematical model of Ca 2ϩ signaling in DVR pericytes to account for the effects of NO and ROS and to predict the degree of vessel contraction.Smooth muscle contraction is initiated by an increase in cytosolic Ca 2ϩ concentration ([Ca] cyt ). Increased binding of Ca 2ϩ to calmodulin (CaM) activates myosin light chain kinase (MLCK), which then phosphorylates myosin light chains (MLC) in the presence of ATP, thereby increasing the cycling rate of actin-myosin cross-bridge formation and generating the active force needed for muscle contraction. Most of the vasodilatory effects of NO on smooth muscle cells appear to be mediated by cGMP. Activity of the NO/cGMP pathway favors reduction in the fraction of phosphorylated myosin, via two different mechanisms: 1) an increase in the activity of myosin light chain phosphatase (MLCP), and 2) modulation of Ca 2ϩ transport that lowers [Ca] cyt , decreases Ca 2ϩ binding to CaM, and thereby reduces MLCK activity.We incorporated these and other signaling pathways in our mathematical model of DVR pericytes as described in MODEL DESCRIPTION. The data on which this and prior versions of the model are based have been largely derived from studies of DVR peric...

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Section: Model Validationsupporting

confidence: 89%

“…14), as well as the magnitude of NO-or ROS-mediated effects on Ca 2ϩ currents (Eqs. [25][26][27][28][29][30][31][32][33][34][35][36][37]. The Ca 2ϩ currents into and out of the SR can then be calculated.…”

Section: Methodsmentioning

confidence: 99%

Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta

Edwards

Cao

Pallone

2011

American Journal of Physiology-Renal Physiology

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“…Recently, an additional mechanism, termed Ca 2ϩ sensitization, has also been suggested in the agonist-induced smooth muscle contraction including airways (6,11,12,24,26,39,60). Although the detailed mechanism is not fully understood, there is increasing evidence that a monomeric GTP-binding protein, RhoA, and its downstream target, Rho-kinase, are involved in the agonistinduced Ca 2ϩ sensitization of airway smooth muscle contraction (11,12,24,60).…”

mentioning

confidence: 99%

Lovastatin inhibits bronchial hyperresponsiveness by reducing RhoA signaling in rat allergic asthma

Chiba

Arima²,

Sakai³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Recent studies revealed an importance of a monomeric GTP-binding protein, RhoA, in contraction of bronchial smooth muscle (BSM). RhoA and its downstream have been proposed as a new target for the treatment of airway hyperresponsiveness in asthma. Statins are known to inhibit the functional activation of RhoA via the depletion of geranylgeranylpyrophosphate. To determine the beneficial effects of statins on the airway hyperresponsiveness in allergic bronchial asthma, we investigated the effects of systemic treatment with lovastatin on the augmented BSM contraction and activation of RhoA in rats with allergic bronchial asthma. Rats were sensitized and repeatedly challenged with 2,4-dinitrophenylated Ascaris suum antigen. Animals were also treated with lovastatin (4 mg kg(-1) day(-1) ip) once a day before and during the antigen inhalation period. Repeated antigen inhalation caused a marked BSM hyperresponsiveness to ACh with the increased expression and translocation of RhoA. Lovastatin treatments significantly attenuated both the augmented contraction and RhoA translocation to the plasma membrane. Lovastatin also reduced the increased cell number in bronchoalveolar lavage fluids and histological changes induced by antigen exposure, whereas the levels of immunoglobulin E in sera and interleukins-4, -6, and -13 in bronchoalveolar lavage fluids were not significantly changed. These findings suggest that lovastatin ameliorates antigen-induced BSM hyperresponsiveness, an important factor of airway hyperresponsiveness in allergic asthmatics, probably by reducing the RhoA-mediated signaling.

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“…The existence of this phenomenon is described in the work of Somlyo and Somlyo. 12 A value of the model parameter u 0 was estimated from the experimental work of Kai et al 13 and Sieck et al 8 ] r are the peak, the plateau, and the resting Ca 2+ concentrations of the signal, respectively. t 1 is the time at the initiation of Ca 2+ increase, t 2 is the time at signal's peak value, and k is the rate constant of its descending phase.…”

Section: Methodsmentioning

confidence: 99%

Mathematical Modeling of the Relation between Myosin Phosphorylation and Stress Development in Smooth Muscles

Fajmut¹,

Dobovišek²,

Brumen³

2005

J. Chem. Inf. Model.

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In this paper the 4-state latch bridge model proposed by Rembold and Murphy is expanded; first by incorporation of the analytical expression of Ca2+ dependent MLCK activation from the work of Kato et al. and second, by inclusion of the myosin dephosphorylation based on the Michaelis-Menten kinetics. The analysis of the proposed model and the comparison with the original model results as well as with the experimental data is presented. The model is able to predict the steady-state isometric stress and the myosin phosphorylation in dependence on steady cytosolic [Ca2+] as well as the temporal evolution of the system in dependence on the input Ca2+ signal in the form of biphasic transient, whereby our model results are in several aspects in better agreement with experimental observations.

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Relationship between force and regulatory myosin light chain phosphorylation in airway smooth muscle

Cited by 16 publications

References 35 publications

Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta

Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta

Lovastatin inhibits bronchial hyperresponsiveness by reducing RhoA signaling in rat allergic asthma

Mathematical Modeling of the Relation between Myosin Phosphorylation and Stress Development in Smooth Muscles

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