Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q16637 (SMA)
 8,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the role of mechanical tension in myofibroblast differentiation using two in vivo rat models. In the first model, granulation tissue was subjected to an increase in mechanical tension by splinting a full-thickness wound with a plastic frame. Myofibroblast features, such as stress fiber formation, expression of ED-A fibronectin and alpha-smooth muscle actin (alpha-SMA) appeared earlier in splinted than in unsplinted wounds. Myofibroblast marker expression decreased in control wounds starting at 10 days after wounding as expected, but persisted in splinted wounds. In the second model, granuloma pouches were induced by subcutaneous croton oil injection; pouches were either left intact or released from tension by evacuation of the exudate at 14 days. The expression of myofibroblast markers was reduced after tension release in the following sequence: F-actin (2 days), alpha-SMA (3 days), and ED-A fibronectin (5 days); cell density was not affected. In both models, isometric contraction of tissue strips was measured after stimulation with smooth muscle agonists. Contractility correlated always with the level of alpha-SMA expression, being high when granulation tissue had been subjected to tension and low when it had been relaxed. Our results support the assumption that mechanical tension is crucial for myofibroblast modulation and for the maintenance of their contractile activity.
 ...
PMID:Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. 1154 93

Myofibroblasts, characterised by high expression of alpha-smooth muscle actin (alpha-SMA), are important and transient cells in normal wound healing but are found in increased number in various pathological conditions of the lung including asthma and pulmonary fibrosis. The mechanisms that regulate the myofibroblast phenotype are unknown but are likely to involve signals from the extracellular matrix transmitted via specific integrins. Vitronectin is a glycoprotein released during inflammation and has been shown to regulate the phenotype of vascular smooth muscle cells via alpha v and beta 1 integrins. In the current study we have examined whether vitronectin influences the phenotype and function of normal human lung fibroblasts (HFL-1). Incubation of HFL-1 cells with vitronectin induced a concentration-dependent reduction in alpha-SMA expression. By contrast, function-blocking monoclonal antibodies to the vitronectin integrins alpha v, beta 1, alpha v beta 3 and alpha v beta 5 induced the expression of alpha-SMA and its organization into stress fibers. Expression of alpha-SMA induced by all function-blocking monoclonal antibodies was abrogated by inhibition of protein kinase C and phosphatidylinositol-3 kinase, but the effects of inhibition of other signalling pathways was integrin dependent. Exposure to other extracellular matrix proteins such as fibronectin, collagen or their integrins did not influence expression of alpha-SMA. The expression and organization of alpha-SMA induced by exposure to function-blocking antibodies was translated into an augmented capacity of HFL-1 cells to contract fibroblast populated collagen gels. By contrast, contraction of collagen gels following incubation with vitronectin was not significantly different to control. This study has shown that vitronectin influences the phenotype and behaviour of HFL-1 cells by downregulating the expression of alpha-SMA and reducing their contractile ability. By contrast, occupancy of specific integrins by function-blocking antibodies upregulated the expression of alpha-SMA and induced the formation of functional stress fibers capable of contracting collagen gels. These results suggest that vitronectin modulates the fibroblast-myofibroblast phenotype, implying an important role in the remodelling process during lung development or response to injury.
 ...
PMID:Regulation of human lung fibroblast phenotype and function by vitronectin and vitronectin integrins. 1168 10

Tubulointerstitial fibrosis is considered to be common endpoint result of many forms of chronic renal diseases. Except for renal replacement, chronic renal fibrosis is presently incurable. This study demonstrates that the combination of hepatocyte growth factor (HGF) gene therapy with inhibition of the renin-angiotensin system produced synergistic beneficial effects leading to dramatic attenuation of renal tubulointerstitial fibrosis in obstructive nephropathy in mice. The combined treatment with human HGF gene and losartan, an angiotensin II (AngII) type I receptor blocker, preserved renal mass and gross morphology of the obstructed kidneys. Although HGF gene therapy alone inhibited the expression of alpha-smooth muscle actin (alpha SMA) by approximately 54% and 60% at day 7 and day 14 after surgery, respectively, its combination with losartan almost completely abolished alpha SMA induction in the obstructed kidneys. The combined therapy also synergistically inhibited the accumulation of interstitial matrix components, such as fibronectin and collagen I, and suppressed renal expression of transforming growth factor-beta1 (TGF-beta1) and its type I receptor. In vitro studies revealed that AngII by itself did not induce alpha SMA, but it drastically potentiated TGF-beta1-initiated alpha SMA expression in tubular epithelial cells. Furthermore, HGF abrogated de novo alpha SMA expression induced by TGF-beta1 plus AngII. These results suggest that many factors are implicated in the pathogenesis of renal interstitial fibrosis; therefore, a combined therapy aimed at simultaneously targeting multiple pathologic pathways may be necessary for halting the progression of chronic renal diseases. These findings may provide the basis for designing future therapeutic regimens for blocking progressive renal fibrosis in patients.
 ...
PMID:Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice. 1223 35

It has been postulated that protein filtered through glomeruli activates tubular epithelial cells, which secrete vasoactive and inflammatory substances including chemokines, leading to tubulointerstitial renal injury. The present study was designed to investigate the role of monocyte chemoattractant protein-1 (MCP-1) in this process and to evaluate the effectiveness of a kidney-targeted gene transfer technique using hydrodynamic pressure. Naked plasmid encoding 7ND (an MCP-1 antagonist) or a control plasmid was introduced into the left kidney of rats. Three days after gene transfer (day 0), intraperitoneal administration of bovine serum albumin (10 mg/g body wt per day) was started and continued for 14 or 21 d. RT-PCR showed that 7ND mRNA was expressed only in the gene-transfected kidney. Immunostaining showed that 7ND protein was localized in the interstitial cells. Macrophage infiltration was significantly reduced in the left kidney of rats treated with 7ND on days 14 and 21. In the right kidney, such effects were not observed. 7ND also attenuated tubular damage and decreased the number of apoptotic cells. Computer-assisted analysis revealed that the areas positively stained for alpha-smooth muscle actin (alpha SMA), fibronectin-EDA, type I collagen, and collagen fibrils were significantly reduced in the 7ND-treated kidney on day 21. Furthermore, 7ND gene therapy significantly reduced MCP-1 and TGF-beta 1 mRNA expression. These results demonstrate that MCP-1 plays an important role in the development of tubulointerstitial inflammation, tubular damage, and fibrosis induced by proteinuria. The fact that 7ND gene therapy had little effect on the contralateral kidney indicates that 7ND acted locally. This strategy may have a potential usefulness as a gene therapy against tubulointerstitial renal injury.
 ...
PMID:Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. 1276 Dec 50

The complex interplay between cells and extracellular matrix (ECM) proteins is critical for lung development. Integrins are key modulators of this interaction. The integrin subunit alpha 8 associates with the beta(1)-subunit to form an RGD-binding integrin. We previously showed that, in adult lung, alpha 8 is expressed in contractile interstitial cells and smooth muscle cells and is upregulated in lung injury. To gain insight into the function of alpha 8 during lung development, we examined the spatiotemporal expression of alpha 8 throughout murine lung development. We compared the distribution of alpha 8 with alpha-smooth muscle actin (alpha SMA), fibronectin (alpha 8 ligand), and cytokeratin. alpha 8 co-localized with alpha SMA and fibronectin in the peribronchial and perivascular regions. In all stages, alpha 8 immunoreactivity was detected diffusely in the mesenchyme except for cells surrounding distal, newly forming airways. alpha 8, alpha SMA, and fibronectin co-localized at tips of secondary septae in the alveolar stage. We conclude that alpha 8 is marker for lung mesenchymal cells starting early in development. alpha 8 is also a marker for smooth muscle cells, expressed as early as alpha SMA. Co-localization of alpha 8 with fibronectin suggests a role in branching morphogenesis. Furthermore, alpha 8 may participate in secondary septation by modulating signals from the extracellular matrix to alveolar myofibroblasts.
 ...
PMID:Expression of the integrin subunit alpha8 in murine lung development. 1450 Jun 99

The purpose of this study was to evaluate specific keratocyte phenotypes (keratocyte, fibroblast, myofibroblast) for cell contractility and ability to contract extracellular matrix. Rabbit keratocyte phenotype was modulated by exposure to optimal proliferative doses of IGF-I, IL-1alpha, FGF2, PDGF-AB, and TGFbeta(1). Cells were then evaluated by immunocytochemistry, western blot, collagen gel contraction and LPA stimulation to measure: (1) focal adhesion (FA), fibronectin (FN) and f-actin assembly; (2) expression of alpha-smooth muscle actin (alpha-SMA); (3) ability to contract extracellular matrix and (4) determine contractile ability, respectively. Untreated keratocytes showed no ability to contract collagen matrix. IGF-I and IL-1alpha increased cell proliferation (70.2 and 74.3%, respectively) but did not alter keratocyte phenotype or ability to contract matrix. FGF2 and PDGF induced fibroblast differentiation with FA and FN assembly and significant (p<0.05) extracellular matrix contraction. TGFbeta(1) induced myofibroblast differentiation with prominent FA and FN assembly, expression of alpha-SMA and significantly greater (p<0.05) matrix contraction. Addition of LPA induced actin filament assembly in growth factor starved fibroblasts and myofibroblasts but had no effect on the cultured keratocyte phenotype. We report for the first time that the keratocyte phenotype is non-contractile and that cell quiescence is not a defining characteristic. We further establish that changes in environmental conditions modulate the keratocyte phenotype resulting in physiologically functional differences regarding cell contractility and capacity to contract extracellular matrix.
 ...
PMID:Modulation of cultured corneal keratocyte phenotype by growth factors/cytokines control in vitro contractility and extracellular matrix contraction. 1455 Apr

Connective tissue growth factor (CTGF) has been reported to play an important role in mediating the profibrotic effects of transforming growth factor-beta (TGF-beta) in the pathogenesis of renal fibrosis. To further elucidate the role of CTGF in renal tubular transdifferentiation and extracellular matrix (ECM) metabolism, we examined the time-course of CTGF, alpha-smooth muscle actin (alpha-SMA), fibronectin and plasminogen activator inhibitor-1(PAI-1) gene expression upon the stimulation of TGF-beta1 (5 microg/L) in cultured human proximal tubular epithelial cell line (HKC), and further investigated the effects of endogenous CTGF blockade. On reverse transcriptional-polymerase chain reaction (RT-PCR) analysis, TGF-beta1 upregulated CTGF gene expression, preceding that of alpha-SMA, fibronectin and PAI-1. The alpha-SMA, fibronectin and PAI-1 mRNA expression induced by TGF-beta1 were significantly inhibited by CTGF antisense oligodeoxynucleotide (ODN) transfection. With prolonged incubation time, CTGF antisense ODN also inhibited intracellular alpha-SMA and PAI-1 protein synthesis, lowered the level of fibronectin and PAI-1 protein secreted into the media, as confirmed by indirect immuno-fluorescence, flow cytometry, enzyme-linked immunosorbent assay (ELISA) and Western blot methods respectively. These results suggested that CTGF may play a crucial role in the renal tubular epithelial-transdifferentiation and the following deposition/degradation process of ECM during tubulointerstitial fibrosis.
 ...
PMID:Role of connective tissue growth factor in renal tubular epithelial-myofibroblast transdifferentiation and extracellular matrix accumulation in vitro. 1513 56

The pathogenesis of cardiac valve disease correlates with the emergence of muscle-like fibroblasts (myofibroblasts). These cells display prominent stress fibers containing alpha-smooth muscle actin (alpha-SMA) and are believed to differentiate from valvular interstitial cells (VICs). However, the biological factors that initiate myofibroblast differentiation and activation in valves remain unidentified. We show that transforming growth factor-beta1 (TGF-beta1) mediates differentiation of VICs into active myofibroblasts in vitro in a dose-dependent manner, as determined by a significant increase in alpha-SMA and the dramatic augmentation of stress fiber formation and alignment. Additionally, TGF-beta1 and increased mechanical stress function synergistically to enhance contractility. In turn, contractile valve myofibroblasts exert tension on the extracellular matrix, resulting in a dramatic realignment of extracellular fibronectin fibrils. TGF-beta1 also inhibits valve myofibroblast proliferation without enhancing apoptosis. Our results are consistent with activation of a highly contractile myofibroblast phenotype by TGF-beta1 and are the first to connect valve myofibroblast contractility with pathological valve matrix remodeling. We suggest that the activation of contractile myofibroblasts by TGF-beta1 may be a significant first step in promoting alterations to the valve matrix architecture that are evident in valvular heart disease.
 ...
PMID:Valvular myofibroblast activation by transforming growth factor-beta: implications for pathological extracellular matrix remodeling in heart valve disease. 1521 6

Renal myofibroblasts play a crucial role in the accumulation of excess extracellular matrix during renal fibrosis. Both transforming growth factor-beta1 (TGFbeta1) and connective tissue growth factor (CTGF) are important profibrotic growth factors, which interact in the pathogenesis of fibrosis. In this study, we demonstrate that CTGF alone has no influence on myofibroblast transformation and fibronectin secretion in kidney interstitial fibroblasts, whereas incubation of CTGF in combination with TGFbeta1 enhanced TGFbeta1 responses, including myofibroblast activation, de novo expression of alpha-SMA, and extracellular accumulation of fibronectin. CTGF induced tryrosine phosphorylation of the cytoplasmic domain of the low-density lipoprotein receptor-associated protein (LRP) in fibroblasts, and the LRP-antagonist, receptor-associated protein (RAP) inhibited CTGF-induced tryrosine phosphorylation of LRP. Inhibition of LRP signaling reduced CTGF-mediated synergistic induction of alpha-SMA protein. Furthermore, the potentiating action of CTGF was neither dependent on modulation of TGFbeta1-induced Smad2 phosphorylation and its association with Smad4, nor did it result from nuclear accumulation of activated Smad2. When TGFbeta1-pretreated fibroblasts were incubated with CTGF, activation of ERK1/2 MAPK signaling was observed. Inhibition of ERK activation by the MEK1 inhibitor PD98059 was associated with a reduction of CTGF-promoted alpha-SMA protein expression. Our in vitro studies provide evidence that CTGF potentiates TGFbeta1-mediated myofibroblast differentiation and activates differentiated myofibroblasts.
 ...
PMID:Tyrosine phosphorylation of the LDL receptor-related protein (LRP) and activation of the ERK pathway are required for connective tissue growth factor to potentiate myofibroblast differentiation. 1546 66

Human fetal cord blood contains subsets of mononuclear cells with the potential to form both hematological and endothelial cells. Vascular progenitor cells, which can produce all three elements of mature blood vessels, including smooth muscle, have been identified in animals. We hypothesized that similar multipotential progenitor cells exist in humans and used the expression of alpha-smooth muscle actin (alpha-SMA) to identify such cells in fetal cord blood. Mononuclear cell preparations were isolated from human umbilical cord blood and CD34(+) and CD133(+) cells obtained by magnetic bead separation. Isolated cells were cultured on fibronectin-coated dishes with medium containing vascular endothelial growth factor, basic fibroblast growth factor, and insulin-like growth factor. mRNA was extracted, and the expression of alpha-SMA and a number of endothelial cell markers (VEGFR-2, vWF, eNOS, VE-Cadhein, PECAM-1 and Tie-2) was determined by reverse transcriptase-PCR techniques. Human umbilical vein endothelial cells (HUVECs) were used as positive controls. Freshly isolated CD34(+) and CD133(+) cells expressed all endothelial cell markers, but did not express alpha-SMA. HUVECs expressed alpha-SMA. Following 4 weeks of culture, CD34(+) isolates produced morphologically endothelial-like cells that expressed both endothelial cell markers and alpha-SMA. CD133(+) cells failed to produce morphological endothelial-like cells but expressed a range of endothelial markers. However, they did not express alpha-SMA. Following culture in an endothelial cell-promoting environment, CD34(+), but not CD133(+), isolates produced endothelial-like cells that expressed alpha-SMA. Human fetal cord blood contains a population of cells that may differentiate toward both an endothelial and a smooth muscle phenotype in culture.
 ...
PMID:Smooth muscle alpha-actin expression in endothelial cells derived from CD34+ human cord blood cells. 1558 9


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>