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PubMed1995

Agonist-independent, muscle-type-specific signal transduction pathways in cat esophageal and lower esophageal sphincter circular smooth muscle.

Smooth muscle cells isolated from the circular muscle layer of cat esophagus and lower esophageal sphincter (LES) exhibit distinct contractile intracellular signal transduction pathways in response to acetylcholine. To determine whether these contractile pathways are muscle type dependent, the authors examined the signal transduction pathways utilized by substance P and bombesin, which in other tissues, use different signal transduction pathways, and by the GTP analog, guanosine 5'-O-3-thiotriphosphate (GTP gamma S), which activates all available G proteins. Western blot analysis of esophageal and LES circular muscle revealed the presence of Gq-G11 (42 kD), Gi1-Gi2 (40 kD) and Go-Gi3 (40 kD) types of G proteins. The responses of esophageal cells to bombesin and substance P were blocked by 1) a Gi3 protein antibody, 2) the inhibitor of specific phosphatidylcholine-phospholipase C (PLC) D609 potassium tricyclo-[5.2.1.0(2.6)]-decyl-(9[8])-xanthogenate, 3) inhibition of phosphatidic acid phosphohydrolase by propranolol, 4) the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7) and 5) incubation in Ca(++)-free medium. Conversely, the responses of LES muscle cells to bombesin and substance P were blocked by 1) a Gq-G11 antibody, 2) a phosphatidylinositol-specific PLC antagonist U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17- yl]amino]hexyl]-1H-pyrrole-2,5-dione), 3) the calmodulin inhibitor CGS9343B (1,3-Dihydro-1-[1-((4-methyl-4H,6H-pyrrolo[1,2-a]-[4,1]benzoxazepin++ +-4 - yl)methyl-4-piperindinyl]-2H-benzimidazol-2-one maleate) and 4) incubation in Sr++. After permeabilization by saponin, inositol 1,4,5-trisphosphate contracted LES but not esophageal cells. The inositol 1,4,5-trisphosphate receptor antagonist heparin and depletion of intracellular Ca++ stores by thapsigargin or A23187 4-Benzoxazolecarboxylic acid, 5-(methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol- 2-yl)ethyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-, [6s-[6.alpha. (2S*,3S*),8.beta. (R*), 9.beta., 11. alpha.]]-(9Cl), blocked bombesin- and substance P-induced contraction of LES but not of esophageal muscle. In addition, contraction in response to GTP gamma S, which activates all G proteins, was blocked in esophageal cells by a Gi3-protein antibody, propranolol, D609 and H7. In LES muscle cells, the response to GTP gamma S was blocked by a Gq protein antibody, U-73122 and CGS934B. These data demonstrate that, in esophageal muscle, different agonists activate the same Gi3 protein, phosphatidylcholine-specific phospholipases and protein kinase C-dependent pathway.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Structure and function of the 10 S conformation of smooth muscle myosin.

Smooth myosin regulatory light chain (RLC) was exchanged with RLC labeled with benzophenone-4-iodoacetamide at Cys-108. Irradiation under conditions that favor the folded (10 S) conformation resulted in 10 S cross-linked myosin that could not unfold. Purified 10 S cross-linked myosin was cross-linked between the RLC of one head to light meromyosin between leucine 1554 and glutamate 1583, adjacent to a predicted noncoiled region, approximately 60 nm from the tip of the tail. At high ionic strength without actin, product release from one-half of the heads was slow (like 10 S) whereas the other half were activated. This suggests that tail binding to the RLC carboxyl-terminal domain stabilizes ionic interactions important to slow nucleotide release. With actin, product release from both (un)phosphorylated 10 S cross-linked myosin was from one slow population similar to unphosphorylated filaments. 10 S cross-linked myosin weakly bound actin (dissociation constant > 500 microM) and did not move actin in vitro. Single-headed myosin did not fold or trap nucleotide. These and other data suggest that "trapping" occurs only with both heads and the tail binds to a newly formed site, which includes the RLC carboxyl-terminal domain, once trapping has occurred.

Actins↗
PubMed1999

Calponin and h-caldesmon in soft tissue tumors: consistent h-caldesmon immunoreactivity in gastrointestinal stromal tumors indicates traits of smooth muscle differentiation.

Currently, the immunohistochemical evaluation of smooth muscle differentiation is usually based on desmin, which also reacts with skeletal muscle and is not present in all smooth muscle tumors, and alpha-smooth muscle actin, which reacts with myoepithelial cells. Neither marker typically reacts with gastrointestinal stromal tumors (GISTs), previously classified as smooth muscle tumors or presently often classified as smooth muscle/stromal tumors. Two cytoskeleton-associated actin-binding proteins, calponin (CALP) and h-caldesmon (HCD), are putative smooth muscle markers that also react with myoepithelia. These markers are of particular interest in the immunohistochemical analysis of tumors; neither of them has been extensively documented in soft tissue tumors. In this study, we evaluated selected normal and reactive tissues and more than 250 mesenchymal tumors for CALP and HCD. Both markers were expressed in parenchymal and vascular smooth muscle cells in various organs and in myoepithelial cells. CALP also reacted with myofibroblasts of desmoplastic stroma. All of our 25 benign smooth muscle tumors from various locations were positive for CALP and HCD, as were most of the retroperitoneal and uterine leiomyosarcomas. HCD was more specific, because CALP also reacted with myofibroblastic lesions. The common reactivity of malignant fibrous histiocytomas with CALP and HCD suggests a combination of myofibroblastic and smooth muscle differentiation in these tumors. The GISTs (c-kit positive, usually actin negative) showed nearly consistent HCD reactivity, suggesting traits of smooth muscle differentiation. GISTs were usually CALP negative and showed a CALP expression pattern similar to that of alpha-smooth muscle actin. Although nonmuscle, nonmyofibroblastic tumors were negative for CALP and HCD, synovial sarcomas showed streaks of CALP-positive cells of unknown significance. CALP and HCD should be explored as markers to identify myofibroblastic and smooth muscle cell differentiation in mesenchymal tumors.

Biomarkers, Tumor↗
PubMed2003

Identification, purification and partial characterization of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in bovine pulmonary artery smooth muscle.

Bovine pulmonary artery smooth muscle tissue possesses the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) as revealed by immunoblot studies of the cytosolic fraction with polyclonal TIMP-1 antibody. In this report, we described the purification and partial characterization of the inhibitor from the cytosolic fraction of the smooth muscle. This inhibitor was purified by a series of anion-exchange, gel filtration and affinity chromatographic procedure. The purified inhibitor showed an apparent molecular mass of 30 kDa in SDS-PAGE. Amino terminal sequence analysis for the first 22 amino acids of the purified inhibitor was also found to be identical to bovine TIMP-1. This glycosylated inhibitor was found to be active against matrix metalloproteinase-9 (MMP-9, gelatinase B), the ambient matrix metalloproteinase in the pulmonary smooth muscle. The purified TIMP-1 was also found to be sensitive to pure rabbit and human fibroblast collagenase and type IV collagenase. In contrast, it had minimum inhibitory activity against bacterial collagenase. It was also found to be inactive against the serine proteases trypsin and plasmin. The inhibitor was heat and acid resistant and it had the sensitivity to trypsin degradation and reduction-alkylation.

Amino Acid Sequence↗
PubMed1990

Concanavalin A- and fetal-calf-serum-induced rounding and myosin light chain phosphorylation in cultured smooth muscle cells.

Rabbit aorta smooth muscle cells (SMC) in long-term culture retracted in less than 10 min in response to a sequential order of stimulations by concanavalin A (Con A) and fetal calf serum (FCS). With additional continuous stimulation by FCS, the SMC took on a circular shape and were anchored to the substrate by retraction fibrils. This rounding was observed only when the cells were sequentially stimulated by Con A and FCS. Depletion of intracellular Ca2+ stores by the addition of EGTA and Ca2+ ionophores inhibited the rounding. Transient phosphorylation of MLC20 was observed in the initial stage during the SMC rounding. The extent of monophosphorylated MLC20 increased for up to 5 min to a maximal value of 49%. The diphosphorylated form reached a maximal value of 29% within 2 min; then both forms of MLC20 decreased. The process of the SMC rounding was inhibited by antimycin A or cytochalasins, in a dose-dependent manner, findings which suggested a dependency on both metabolic energy and actin-containing microfilaments. The smooth-muscle-relaxing agent, HA1077, also inhibited the process of SMC rounding. These observations suggest that a cellular contractile process might be involved in rounding of SMC.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

[Non-congenital smooth muscle hamartoma: 3 cases].

BACKGROUND: Smooth-muscle hamartoma is an uncommon, usually congenital cutaneous hyperplasia of the arrectores pilorum muscles. When it is acquired, it may be confused with Becker's nevus with a prominent smooth-muscle component. Both entities can be considered polar forms of a spectrum of dermal smooth muscle hyperplasia. We report three cases of acquired smooth-muscle hamartoma in adult patients. CASE REPORTS: Three healthy women in their fifties presented with adult-onset asymptomatic, multiple small papules grouped on circumscribed areas of the trunk. Results of biopsy specimens showed an excess of haphazardly oriented smooth-muscle bundles in the mid to lower dermis with an unremarkable overlying epidermis. Immunohistochemical studies showed two components in this proliferation: a smooth muscle cell population expressing vimentin and smooth muscle actin, and another population of CD34 positive dendritic cells, interspersed among the former. DISCUSSION: Proliferation of CD34+ dermal dendritic cells has been recently described as an additional component in the proliferation of smooth muscle cells, hair follicles and nerve fascicles that constitute congenital smooth muscle hamartomas. The results of immunohistochemical studies in our three cases extend this observation to the acquired variant of cutaneous smooth muscle hamartoma, which can be included in the expanding spectrum of diseases, recently characterized by the presence of a dermal proliferation of CD34 + cells.

Female↗
PubMed2001

Differential binding of an SRF/NK-2/MEF2 transcription factor complex in normal versus neoplastic smooth muscle tissues.

The malignant potential of smooth muscle tumors correlates strongly with the disappearance of gamma-smooth muscle isoactin, a lineage-specific marker of smooth muscle development. In this paper, we identify a 36-base pair regulatory motif containing an AT-rich domain, CArG box, and a non-canonical NK-2 homeodomain-binding site that has the capacity to regulate smooth muscle-specific gene expression in cultured intestinal smooth muscle cells. Serum-response factor associates with an NK-2 transcription factor via protein-protein interactions and binds to the core CArG box element. Our studies suggest that the NK-2 transcription factor that associates with serum-response factor during smooth muscle differentiation is Nkx2-3. Myocyte-specific enhancer factor 2 binding to this regulatory complex was also observed but limited to uterine smooth muscle tissues. Smooth muscle neoplasms displayed altered transcription factor binding when compared with normal myometrium. Differential nuclear accessibility of serum-response factor protein during smooth muscle differentiation and neoplastic transformation was also observed. Thus, we have identified a unique regulatory complex whose differential binding properties and nuclear accessibility are associated with modulating gamma-smooth muscle isoactin-specific gene expression in both normal and neoplastic tissues.

3T3 Cells↗
PubMed1994

Differential isoactin gene expression in the sphincteric and nonsphincteric gastrointestinal smooth muscles of the opossum.

The sphincteric smooth muscle tissues of the gastrointestinal tract have been shown to possess mechanical properties distinct from the surrounding nonsphincteric smooth muscle tissues. Little is currently known regarding the molecular basis of this differential smooth muscle development and function. Actin is an important contractile protein whose expression has been linked to the normal development and function of smooth muscle tissues. The purpose of this study was to characterize isoactin gene expression in the sphincteric versus nonsphincteric smooth muscle tissues of the gastrointestinal tract. Northern blot analysis was performed on manometrically identified sphincteric and the flanking nonsphincteric smooth muscle tissues of the adult opossum. Quantitative analysis revealed a distinct pattern of isoactin gene expression in the sphincteric versus nonsphincteric smooth muscle tissues of the gut. The sphincteric smooth muscle tissues expressed significantly lower total quantities of isoactin mRNA than their surrounding nonsphincteric smooth muscle tissues. It is hypothesized that these differential patterns of isoactin gene expression may play a significant role in establishing the myogenic potential of the functionally distinct sphincteric and nonsphincteric smooth muscle tissues of the gut.

Actins↗
PubMed2000

The contractile apparatus and mechanical properties of airway smooth muscle.

The functional properties of airway smooth muscle are fundamental to the properties of the airways in vivo. However, many of the distinctive characteristics of smooth muscle are not easily accounted for on the basis of molecular models developed to account for the properties of striated muscles. The specialized ultrastructural features and regulatory mechanisms present in smooth muscle are likely to form the basis for many of its characteristic properties. The molecular organization and structure of the contractile apparatus in smooth muscle is consistent with a model of force generation based on the relative sliding of adjacent actin and myosin filaments. In airway smooth muscle, actomyosin activation is initiated by the phosphorylation of the 20 kDa light chain of myosin; but there is conflicting evidence regarding the role of myosin light chain phosphorylation in tension maintenance. Tension generated by the contractile filaments is transmitted throughout the cell via a network of actin filaments anchored at dense plaques at the cell membrane, where force is transmitted to the extracellular matrix via transmembrane integrins. Proteins bound to actin and/or localized to actin filament anchorage sites may participate in regulating the shape of the smooth muscle cell and the organization of its contractile filament system. These proteins may also participate in signalling pathways that regulate the crossbridge activation and other functions of the actin cytoskeleton. The length-dependence of active force and the mechanical plasticity of airway smooth muscle may play an important role in determining airway responsiveness during lung volume changes in vivo. The molecular basis for the length-dependence of tension in smooth muscle differs from that in skeletal muscle, and may involve mechano-transduction mechanisms that modulate contractile filament activation and cytoskeletal organization in response to changes in muscle length. The reorganization of contractile filaments may also underlie the plasticity of the mechanical response of airway smooth muscle. Changes in the structural organization and signalling pathways of airway smooth muscle cells resulting form alterations in mechanical forces in the lung may be important factors in the development of pathophysiological conditions of chronic airway hyperresponsiveness.

Animals↗
PubMed1997

Mechanisms for the mechanical response of airway smooth muscle to length oscillation.

Airway smooth muscle tone in vitro is profoundly affected by oscillations in muscle length, suggesting that the effects of lung volume changes on airway tone result from direct effects of stretch on the airway smooth muscle. We analyzed the effect of length oscillation on active force and length-force hysteresis in canine tracheal smooth muscle at different oscillation rates and amplitudes during contraction with acetylcholine. During the shortening phase of the length oscillation cycle, the active force generated by the smooth muscle decreased markedly below the isometric force but returned to isometric force as the muscle was lengthened. Results indicate that at rates comparable to those during tidal breathing, active shortening and yielding of contractile elements contributes to the modulation of force during length oscillation; however, the depression of force during shortening cannot be accounted for by cross-bridge properties, shortening-induced cross-bridge deactivation, or active relaxation. We conclude that the depression of contractility may be a function of the plasticity of the cellular organization of contractile filaments, which enables contractile element length to be reset in relation to smooth muscle cell length as a result of smooth muscle stretch.

Acetylcholine↗