Invited Review: Cross-bridge regulation by thin filament-associated proteins

Morgan, Kathleen G.; Gangopadhyay, Samudra S.

doi:10.1152/jappl.2001.91.2.953

Cited by 210 publications

(218 citation statements)

References 112 publications

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“…RNA was extracted from lung fibroblasts and subjected to genome-wide expression analysis by using U133A arrays (Affymetrix). ET-1 induced several transcripts that encoded genes expected to contribute to the contractile phenotype of myofibroblasts (Table 1), including mRNAs encoding smooth muscle alpha and ␥-actins, contraction promoting proteins, and smooth muscle actin-associated cytoskeletal proteins such as caldesmon, gelsolin, tensin, and filamin (Table 1; Janson et al, 1991;Morgan and Gangopadhyay, 2001). In addition, transcripts encoding ezrin, radixin, and moesin, proteins that cross-link actin to the plasma membrane (Louvet-Vallee, 2000), were found to be induced by ET-1 (Table 1).…”

Section: Et-1 Induces Expression Of Procontractile Proteins In Lung Fmentioning

confidence: 99%

Endothelin-1 Promotes Myofibroblast Induction through the ETA Receptor via a rac/Phosphoinositide 3-Kinase/Akt-dependent Pathway and Is Essential for the Enhanced Contractile Phenotype of Fibrotic Fibroblasts

Chen

Denton

et al. 2004

MBoC

326

307

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The endothelins are a family of endothelium-derived peptides that possess a variety of functions, including vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and promotes myofibroblast contraction and migration, hence contributing to matrix remodeling during tissue repair. Here, we show that addition of ET-1 to normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including ␣-smooth muscle actin (␣-SMA), ezrin, moesin, and paxillin. We confirm that ET-1 enhances the ability of lung fibroblasts to contract extracellular matrix, a function essential for tissue repair, through induction of de novo protein synthesis. Blockade of the Akt/ phosphoinositide 3-kinase (PI3-kinase) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce ␣-SMA, ezrin, paxillin, and moesin and to promote matrix contraction. Dominant negative rac and Akt blocked the ability of ET-1 to promote formation of ␣-SMA stress fibers. Using specific ET-1 receptor inhibitors, we show that ET-1 induces collagen matrix contraction through the ETA, but not the ETB, receptor. Relative to normal pulmonary fibroblasts, fibroblasts cultured from scars of patients with the fibrotic disease systemic sclerosis (scleroderma) show enhanced ET-1 expression and binding. Systemic sclerosis lung fibroblasts show increased ability to contract a collagen matrix and elevated expression of the procontractile proteins ␣-SMA, ezrin, paxillin, and moesin, which are greatly reduced by antagonizing endogenous ET-1 signaling. Thus, blocking ET-1 or the PI3-kinase/Akt cascades might be beneficial in reducing scar formation in pulmonary fibrosis. INTRODUCTIONA complex histological and architectural structure is a prerequisite for effective lung function. In the lung, specialized structures, the alveoli, increase the surface area of the lung, allowing for efficient gas exchange. The maintenance of these specialized structures is in turn dependent on the underlying connective tissue, comprised principally of fibroblasts and extracellular matrix (ECM; for review, see Gadek et al., 1984), which is essential for the mechanical and structural integrity of the lung. As a response to environmental insults, or as a consequence of local inflammatory processes, structural damage to the lung can occur, resulting in a wound healing response. This response consists of an integrated series of biochemical, immunological, and structural changes that result in the de novo synthesis of a new epithelium, blood vessels, and connective tissue (Razzaque and Taguchi, 2003). The proper repair of connective tissue requires synthesis of new ECM components, such as collagen and fibronectin (Badylak, 2002). In addition, repair of connective tissue requires the proper reconstitution of its support function; that is, an appropriate tensile strength must be recreated. This tensile strength results from the remodeling of the newly formed ECM through a combination of cell locomotion and translocation of the flexible collage...

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Section: Et-1 Induces Expression Of Procontractile Proteins In Lung Fmentioning

confidence: 99%

Endothelin-1 Promotes Myofibroblast Induction through the ETA Receptor via a rac/Phosphoinositide 3-Kinase/Akt-dependent Pathway and Is Essential for the Enhanced Contractile Phenotype of Fibrotic Fibroblasts

Chen

Denton

et al. 2004

MBoC

326

307

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“…The biochemical activity of h1-calponin in inhibiting smooth muscle actomyosin ATPase has been extensively investigated (9,12). Structural conservation suggests that h1-and h2-calponins may function via similar mechanisms in the regulation of actin-myosin-based cell motility.…”

Section: H2-calponin Is Found In Tissues Under Mechanical Tensionmentioning

confidence: 99%

Cytoskeletal Tension Regulates Both Expression and Degradation of h2-Calponin in Lung Alveolar Cells

Hossain

Smith

et al. 2006

Biochemistry

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Calponin is an actin filament-associated regulatory protein and its h2 isoform is expressed in lung alveolar epithelial cells under postnatal up-regulation during lung development corresponding to the commencement of respiratory expansion. Consistent with this correlation to mechanical tension, the expression of h2-calponin in alveolar cells is dependent on substrate stiffness and cytoskeleton tension. The function of h2-calponin in the stability of actin cytoskeleton implicates a role in balancing the strength and compliance of alveoli. An interesting finding is a rapid degradation of h2-calponin in lung after prolonged deflation, which is prevented by inflation of the lung to the in situ expanded volume. Decreasing mechanical tension in cultured alveolar cells by reducing the dimension of culture matrix reproduced the degradation of h2-calponin. Inhibition of myosin II ATPase also resulted in the degradation of h2-calponin in alveolar cells, showing a determining role of the tension in the actin cytoskeleton. Alveolar cells statically cultured on silicon rubber membrane build high tension in the cytoskeleton corresponding to a high expression of h2-calponin. Chronic cyclic stretching of cells on the membrane did not increase but decreased the expression of h2-calponin. This finding suggests that when cellular structure adapted to the stretched dimension, cyclic relaxations periodically release cytoskeleton tension and lower the total amount of tension that the cell senses over time. Therefore, the isometric tension, other than tension dynamics, determines the expression of h2-calponin. The tension regulation of h2-calponin synthesis and degradation demonstrate a novel mechanical regulation of cellular biochemistry.Living cells respond to mechanical forces by changes in cellular structure and function through gene regulation and posttranslational protein modification (1)(2)(3)(4)(5). Reorganization of the cytoskeleton is a key component of the cellular response to mechanical stimuli (3,6). The actin cytoskeleton is a dynamic filamentous network that determines cell shape and strength and plays an important role in cellular response to mechanical tension (7). Calponin is an actin filament-associated regulatory protein (8) and has been extensively studied for its role in the contractility of smooth muscle (9,10). Biochemical activities of calponin have been documented in details mainly from experiments using the h1 isoform in smooth muscles (11). Through high affinity binding to F-actin, calponin inhibits the actin-activated smooth muscle myosin MgATPase and the production of force (12). Despite the extensive investigations, the physiological function of calponin in living cells remains to be established.The h2 isoform of calponin (11) is found in smooth muscle and non-muscle cells. Calponin's association with actin stress fibers and function in regulating actin-myosin interaction suggest † This study was supported by grants from the National Institutes of Health (AR048816 and HL078773).*To whom correspon...

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“…Activation of ERK has been shown to be involved in the mechanism of vasoconstriction in a number of blood vessels in response to different agonists [6, 13 16]. The mechanism through which ERK causes vasoconstriction has been suggested to be through phosphorylation and hence inhibition of caldesmon [11]. Caldesmon inhibits the myosin ATPase.…”

Section: Introductionmentioning

confidence: 99%

Pre-contraction with the thromboxane-mimetic U46619 enhances P2X receptor-mediated contractions in isolated porcine splenic artery

Roberts

2011

Purinergic Signalling

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We have previously demonstrated that the thromboxane-mimetic U46619 enhances α 2 -adrenoceptormediated contractions through increased activation of extracellular signal-regulated kinase (ERK). In this study, we determined whether U46619 also enhances P2X-mediated contractions through the same pathway. Segments of porcine splenic artery were mounted in isolated tissue baths. Tissues were pre-contracted with U46619 to 10-20% of the response to 60 mM KCl prior to addition of α,β-methylene ATP (P2X receptor agonist). The effect of inhibition of ERK activation with the mitogen-activated protein (MAP)/ERK kinase inhibitor PD98059 (50 μM), Rho kinase inhibition with Y27632 (10 μM), p38 MAP kinase with SB203580 (10 μM) or L-type calcium channels with nifedipine (1 μM) on both the direct and enhanced contractions was then determined. U46619 enhanced the contractions to α,β-methylene ATP. Although PD98059 inhibited the direct contractions to α,β-methylene ATP, it had no effect on the U46619-enhanced contractions. Similarly, Y27632 and SB203580 inhibited the direct contractions to α,β-methylene ATP, but had no effect on the enhanced contractions. Nifedipine inhibited the responses to α,β-methylene ATP in the absence and presence of U46619. This study demonstrates that precontraction with U46619 enhances P2X-mediated contractions in the porcine splenic artery through a mechanism independent of ERK, Rho kinase and p38 MAP kinase. Further studies are required to determine the exact mechanism involved.

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Invited Review: Cross-bridge regulation by thin filament-associated proteins

Cited by 210 publications

References 112 publications

Endothelin-1 Promotes Myofibroblast Induction through the ETA Receptor via a rac/Phosphoinositide 3-Kinase/Akt-dependent Pathway and Is Essential for the Enhanced Contractile Phenotype of Fibrotic Fibroblasts

Endothelin-1 Promotes Myofibroblast Induction through the ETA Receptor via a rac/Phosphoinositide 3-Kinase/Akt-dependent Pathway and Is Essential for the Enhanced Contractile Phenotype of Fibrotic Fibroblasts

Cytoskeletal Tension Regulates Both Expression and Degradation of h2-Calponin in Lung Alveolar Cells

Pre-contraction with the thromboxane-mimetic U46619 enhances P2X receptor-mediated contractions in isolated porcine splenic artery

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