Time Course of Airway Mechanics of the (+)Insert Myosin Isoform Knockout Mouse

Tuck, Stephanie A.; Maghni, Karim; Poirier, Annie; Babu, Gopal J.; Periasamy, Muthu; Bates, Jason H. T.; Léguillette, Renaud; Lauzon, Anne‐Marie

doi:10.1165/rcmb.2003-0254oc

Cited by 23 publications

(18 citation statements)

References 37 publications

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“…Only SM-B expression was significantly reduced at the protein level, 7 days after repeated challenges in OVA-sensitized/OVA-challenged rats, suggesting the possibility of a selective downregulation of this protein. The 7-amino acid insertion at the NH 2 -terminal sequence of the SM-B isoform accounts for an increase in contractile velocity at the molecular level compared with other myosin isoforms in an in vitro motility assay (15), and a SM-B knockout mouse has demonstrated differences in the kinetics of bronchoconstriction (33). Also, as demonstrated with bladder myocytes, the expression of SM-B is largely reduced during the proliferation phase of in Fig.…”

Section: Discussionmentioning

confidence: 94%

“…To date, there has been no clear phenotypic modulation of the kind we appear to have found. The analysis of mRNA isolated from lasermicrodissected SM from mild to moderate asthmatic subjects showed little change in myosin heavy chain or MLCK (33), whereas in another study of mild asthmatics there was both a significant increase in myosin heavy chain, in particular the SM-B isoform, and a very modest increase in MLCK (18). The loss of the contractile proteins as a result of hyperplasia of SM is less likely to be detected in mild asthma as it is likely that few SM cells are affected by hyperplasia at any given time.…”

Section: Discussionmentioning

confidence: 98%

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The effects of repeated allergen challenge on airway smooth muscle structural and molecular remodeling in a rat model of allergic asthma

Labonté

Hassan

Risse

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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The effects of remodeling of airway smooth muscle (SM) by hyperplasia on airway SM contractility in vivo are poorly explored. The aim of this study was to investigate the relationship between allergen-induced airway SM hyperplasia and its contractile phenotype. Brown Norway rats were sensitized with ovalbumin (OVA) or saline on day 0 and then either OVA-challenged once on day 14 and killed 24 h later or OVA-challenged 3 times (on days 14, 19, and 24) and killed 2 or 7 days later. Changes in SM mass, expression of total myosin, SM myosin heavy chain fast isoform (SM-B) and myosin light chain kinase (MLCK), tracheal contractions ex vivo, and airway responsiveness to methacholine (MCh) in vivo were assessed. One day after a single OVA challenge, the number of SM cells positive for PCNA was greater than for control animals, whereas the SM mass, contractile phenotype, and tracheal contractility were unchanged. Two days after three challenges, SM mass and PCNA immunoreactive cells were increased (3-and 10-fold, respectively; P Ͻ 0.05), but airway responsiveness to MCh was unaffected. Lower expression in total myosin, SM-B, and MLCK was observed at the mRNA level (P Ͻ 0.05), and total myosin and MLCK expression were lower at the protein level (P Ͻ 0.05) after normalization for SM mass. Normalized tracheal SM force generation was also significantly lower 2 days after repeated challenges (P Ͻ 0.05). Seven days after repeated challenges, features of remodeling were restored toward control levels. Allergen-induced hyperplasia of SM cells was associated with a loss of contractile phenotype, which was offset by the increase in mass. phenotype; animal model; myosin heavy chain isoform STRUCTURAL AIRWAY REMODELING has been widely reported in both human asthma (4, 13) and animal models of experimental asthma (11,23,37). Most tissues of the airway wall are affected by remodeling, and the observed changes include shedding of the epithelium, thickening of the reticular basement membrane, increased mucus gland size and number, goblet cell differentiation, angiogenesis, and augmentation of the airway smooth muscle (SM) mass (4). The changes in airway wall tissues are likely to be of clinical importance since they may control airway caliber, airway elasticity, and responsiveness and may cause symptoms related to mucus overproduction (4). Airway SM remodeling is a reported feature of several animal models of allergic asthma (11,12,22), including the Brown Norway (BN) rat (19,26,31). The increase in SM mass, observed in asthma of varying severity (5, 29, 36), has been proposed to be sufficient to account for altered airway responsiveness (16). The augmentation of airway SM mass has been attributed to hyperplasia through evidence of cell proliferation quantified by bromodeoxyuridine incorporation or PCNA expression in vivo (11,19,28,37). Susceptibility to SM remodeling may be a risk factor for asthma; cultured airway SM cells from asthmatic subjects were shown to have a higher proliferation rate than cells from normal subjects (14), sim...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 98%

The effects of repeated allergen challenge on airway smooth muscle structural and molecular remodeling in a rat model of allergic asthma

Labonté

Hassan

Risse

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A (ϩ)insert SMMHC knockout mouse (3) confirmed the critical role of the insert in smooth muscle contractility. Notably, we showed (41) alterations in the time course of bronchoconstriction in these knockout mice. Although the presence of the fast (ϩ)insert isoform and its role in animal models of disease have received enormous attention, its expression in human smooth muscle has never been demonstrated.…”

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confidence: 75%

(+)Insert smooth muscle myosin heavy chain (SM-B) isoform expression in human tissues

Léguillette

Gil

Zitouni

et al. 2005

American Journal of Physiology-Cell Physiology

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Animal studies show that the (ϩ)insert isoform is predominantly expressed in rapidly contracting phasic muscle and the (Ϫ)insert isoform is mostly found in slowly contracting tonic muscle. The expression of the (ϩ)insert isoform has never been demonstrated in human smooth muscle. We hypothesized that the (ϩ)insert isoform is present in humans and that its expression is commensurate with the organ's functional requirements. We report, for the first time, the sequence of the human (ϩ)insert isoform and quantification of its expression by real-time PCR and Western blot analysis in a panel of human organs. The (ϩ)insert isoform mRNA and protein expression levels are significantly greater in small intestine compared with all organs studied except for trachea and are significantly greater in trachea compared with uterus and aorta. To assess the functional significance of this differential myosin isoform expression between organs, we measured the rate of actin filament movement ( max) when propelled by myosin purified from rat organs, because the rat and human inserts are identical and their remaining sequences show 93% identity. max exhibits a rank correlation from the most tonic to the most phasic organ. The selective expression of the (ϩ)insert isoform observed among human organs suggests that it is an important determinant of tissue shortening velocity. A differential expression of the (ϩ)insert isoform could also account for altered contractile properties observed in human pathology. phasic and tonic smooth muscle; real-time polymerase chain reaction; in vitro motility assay SMOOTH MUSCLE IS FOUND in all hollow organs of the mammalian organism, and its function ranges from tone maintenance to content propulsion. Many studies point to the smooth muscle myosin heavy chain (SMMHC) as an important element contributing to these diverse contractile properties (see Ref. 16 for review). SMMHC is made up of a globular head, containing an ATPase site and an actin binding domain, and an ␣-helical tail to which regulatory and essential light chains are bound. SMMHC isoforms are generated by alternative splicing from a single gene (1,9,33,46). Four SMMHC isoforms have been described in various animal species. The first two isoforms identified differ in the carboxy terminus by distinct sequences of 43 (SM1) or 9 (SM2) amino acids (2, 33). The next two isoforms differ in the amino terminus by the presence [(ϩ)insert] or absence [(Ϫ)insert] of a seven-amino acid insert in a surface loop above the ATPase site (18, 46). The (ϩ) and (Ϫ)insert isoforms are also commonly referred to as SM-B and SM-A, respectively. All combinations of these isoforms are possible, i.e., (ϩ)insert SM1, (ϩ)insert SM2, (Ϫ)insert SM1, and (Ϫ)insert SM2. No difference in molecular mechanics has been observed between SM1 and SM2, but, as shown with myosin constructs, the sole presence of the amino-terminal insert doubles the actin-activated ATPase activity and the rate of actin filament movement ( max ) in the in vitro motility assay (17,22,36). Because of t...

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“…Moreover, strains of rats with hyperreactive airways have constitutive increased expression of the (+)insert isoform, 10 and knockout mice exhibit a slower time course of bronchoconstriction. 11 Interestingly, in the urinary bladder and intestine, the (+)insert isoform expression decreases with urethral and…”

Section: -4mentioning

confidence: 99%

Inhaled corticosteroids modulate the (+)insert smooth muscle myosin heavy chain in the equine asthmatic airways

Boivin

Vargas

Lefebvre-Lavoie

et al. 2014

Thorax

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Rationale Overexpression of the (+)insert smooth muscle myosin heavy chain (SMMHC) isoform could contribute to airway bronchospasm by increasing the velocity of contraction. Whether the (+)insert isoform is present in the small airways and its expression is reversible in asthma are unknown. Objectives To determine the anatomical location and the expression kinetics of the (+)insert SMMHC isoform in airways of horses with heaves and to evaluate its modulation in response to disease status. Methods We evaluated the (+)insert SMMHC isoform in the airways of horses with heaves during disease exacerbation and remission, and in controls. The expression kinetics of the SMMHC (+)insert was then assessed at multiple time points in two studies: first, in horses with heaves treated for a 1-year period with antigen avoidance alone, inhaled corticosteroids alone or both; second, in horses with heaves before and after a 30-day natural antigen exposure. Gene expression analysis was assessed by quantitative PCR and protein expression was confirmed by targeted mass spectrometry. Measurements and main results The (+)insert SMMHC isoform was significantly increased in central and peripheral airways, but not in the trachea of heavesaffected horses in clinical exacerbation when compared horses with heaves in remission and controls. Both corticosteroid administration and antigen avoidance led to a significant reduction of the (+)insert expression in the airways. The (+)insert SMMHC isoform was not significantly increased in airways after 1 month of antigenic re-exposure. Conclusions The (+)insert SMMHC expression is increased throughout the bronchial tree in horses with heaves and reversible by corticosteroids administration and antigen avoidance.

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Time Course of Airway Mechanics of the (+)Insert Myosin Isoform Knockout Mouse

Cited by 23 publications

References 37 publications

The effects of repeated allergen challenge on airway smooth muscle structural and molecular remodeling in a rat model of allergic asthma

The effects of repeated allergen challenge on airway smooth muscle structural and molecular remodeling in a rat model of allergic asthma

(+)Insert smooth muscle myosin heavy chain (SM-B) isoform expression in human tissues

Inhaled corticosteroids modulate the (+)insert smooth muscle myosin heavy chain in the equine asthmatic airways

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