Caveolin-1 and force regulation in porcine airway smooth muscle

Sathish, Venkatachalem; Yang, Binxia; Meuchel, Lucas W.; VanOosten, Sarah Kay; Ryu, Alexander J.; Thompson, Michael A.; Prakash, Y. S.; Pabelick, Christina M.

doi:10.1152/ajplung.00322.2010

Cited by 30 publications

(25 citation statements)

References 78 publications

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“…PDE5 activity was also cross regulated by contractile agonist via PKC-mediated inhibition of protein phosphatase 1, leading to augmentation of PDE5 activity and inhibition of cGMP levels (29). PDE5 is specific for the degradation of cGMP and has no effect on the degradation of cAMP (6,9,27,44).…”

Section: Discussionmentioning

confidence: 99%

Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1^−/− mice impair the peristaltic reflex and propulsion

Mahavadi

Bhattacharya²,

Kumar³

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Murthy KS. Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1 Ϫ/Ϫ mice impair the peristaltic reflex and propulsion. Am J Physiol Gastrointest Liver Physiol 305: G964 -G974, 2013. First published October 24, 2013 doi:10.1152/ajpgi.00165.2013.-Caveolae are specialized regions of the plasma membrane that concentrate receptors and associated signaling molecules critical in regulation of cellular response to transmitters and hormones. We have determined the effects of caveolin-1 (Cav-1) deletion, caveolin-1 siRNA, and caveolar disruption in mice on the signaling pathways that mediate contraction and relaxation in colonic smooth muscle and on the components of the peristaltic reflex in isolated tissue and propulsion in intact colonic segments. In Cav-1 Ϫ/Ϫ mice, both relaxation and contraction were decreased in smooth muscle cells and muscle strips, as well as during both phases of the peristaltic reflex and colonic propulsion. The decrease in relaxation in response to the nitric oxide (NO) donor was accompanied by a decrease in cGMP levels and an increase in phosphodiesterase 5 (PDE5) activity. Relaxation by a PDE5-resistant cGMP analog was not affected in smooth muscle of Cav-1 Ϫ/Ϫ mice, suggesting that inhibition of relaxation was due to augmentation of PDE5 activity. Similar effects on relaxation, PDE5 and cGMP were obtained in muscle cells upon disruption of caveolae by methyl-␤-cyclodextrin or suppression of Cav-1. Sustained contraction mediated via inhibition of myosin light chain phosphatase (MLCP) activity is regulated by Rho kinase and PKC via phosphorylation of two endogenous inhibitors of MLCP: myosin phosphatasetargeting subunit (MYPT1) and 17-kDa PKC-potentiated protein phosphatase 1 inhibitor protein (CPI-17), respectively. The activity of both enzymes and phosphorylation of MYPT1 and CPI-17 were decreased in smooth muscle from Cav-1 Ϫ/Ϫ mice. We conclude that the integrity of caveolae is essential for contractile and relaxant activity in colonic smooth muscle and the maintenance of neuromuscular function at organ level.caveolin; phosphodiesterase; Rho kinase; smooth muscle; peristaltic reflex CAVEOLAE AND THEIR MAIN MEMBRANE PROTEINS, caveolin-1 (Cav-1), -2, and -3, form regular invaginations of the plasma membrane, which are sites that concentrate receptors, G proteins, effector enzymes, and associated signaling molecules in several cell types (reviewed in Refs. 2, 4, 22, 37, 50). As such, they play a critical role in regulating, either by augmenting or inhibiting, the physiological response of cells to transmitters and hormones. Most studies have concentrated on identifying their role in regulating the response to agonists at the cellular level; however, the translation of these cellular effects of caveolin to the organ level is less well understood although many roles have been postulated (1, 25, 43-45, 50, 58).In the gut, caveoli are present on many cell types, including smooth muscle cells, interstitial cells of Cajal (ICC), and endothelial cell...

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Section: Discussionmentioning

confidence: 99%

Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1^−/− mice impair the peristaltic reflex and propulsion

Mahavadi

Bhattacharya²,

Kumar³

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In this regard, we and others have previously demonstrated in vitro that the plasma membrane of human ASM cells contain caveolae (flask-shaped invaginations) that express the constituent scaffolding proteins caveolin-1 and -2 (but not caveolin-3) (15,17,41). Importantly, caveolae harbor plasma membrane proteins involved in regulation of [Ca 2ϩ ] i as well as force (17,41,48) and may thus be key regulators of ASM contractility. Indeed, we previously demonstrated that reduced caveolin-1 expression decreases ASM [Ca 2ϩ ] i and contractility (46,48), whereas proinflammatory cytokines such as TNF-␣ and IL-13 increase caveolin-1 expression, which in turn contributes to the enhanced [Ca 2ϩ ] i response of human ASM during inflammation (46).…”

mentioning

confidence: 88%

“…Importantly, caveolae harbor plasma membrane proteins involved in regulation of [Ca 2ϩ ] i as well as force (17,41,48) and may thus be key regulators of ASM contractility. Indeed, we previously demonstrated that reduced caveolin-1 expression decreases ASM [Ca 2ϩ ] i and contractility (46,48), whereas proinflammatory cytokines such as TNF-␣ and IL-13 increase caveolin-1 expression, which in turn contributes to the enhanced [Ca 2ϩ ] i response of human ASM during inflammation (46). Separately, other investigators have demonstrated that suppression of caveolin-1 is associated with a proliferative ASM cell phenotype (16,22), another key component of asthma.…”

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confidence: 99%

Caveolin-1 knockout mice exhibit airway hyperreactivity

Aravamudan

VanOosten

Meuchel

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Although caveolins have been found in endothelium and epithelium (where they regulate nitric oxide synthase activity), their role in smooth muscle is still under investigation. We and others have previously shown that caveolae of human airway smooth muscle (ASM), which express caveolin-1, contain Ca 2ϩ and force regulatory proteins and are involved in mediating the effects of inflammatory cytokines such as TNF-␣ on intracellular Ca 2ϩ concentration responses to agonist. Accordingly, we tested the hypothesis that in vivo, absence of caveolin-1 leads to reduced airway hyperresponsiveness, using a knockout (KO) (Cav1 KO) mouse and an ovalbumin-sensitized/challenged (OVA) model of allergic airway hyperresponsiveness. Surprisingly, airway responsiveness to methacholine, tested by use of a FlexiVent system, was increased in Cav1 KO control (CTL) as well as KO OVA mice, which could not be explained by a blunted immune response to OVA. In ASM of wild-type (WT) OVA mice, expression of caveolin-1, the caveolar adapter proteins cavins 1-3, and caveolae-associated Ca 2ϩ and force regulatory proteins such as Orai1 and RhoA were all increased, effects absent in Cav1 KO CTL and OVA mice. However, as with WT OVA, both CTL and OVA Cav1 KO airways showed signs of enhanced remodeling, with high expression of proliferation markers and increased collagen. Separately, epithelial cells from airways of all three groups displayed lower endothelial but higher inducible nitric oxide synthase and arginase expression. Arginase activity was also increased in these three groups, and the inhibitor nor-NOHA (N-omega-nor-L-arginine) enhanced sensitivity of isolated tracheal rings to ACh, especially in Cav1 KO mice. On the basis of these data disproving our original hypothesis, we conclude that caveolin-1 has complex effects on ASM vs. epithelium, resulting in airway hyperreactivity in vivo mediated by altered airway remodeling and bronchodilation. Overall, in vitro data clearly demonstrate an important role for caveolin-1 in enhanced airway contractility relevant to asthma. However, the effect of altered caveolin-1 expression or function in vivo has not been examined and was the focus of this study. Based on previous work, our hypothesis was that reduced caveolin-1 results in airway hyporesponsiveness. To this end we employed the mouse lacking caveolin-1 (Cav1 KO) as a model, with ovalbumin (OVA) sensitization and challenge as a model of allergic airway hyperresponsiveness to test our hypothesis. Cav1 KO mice are known to develop pulmonary fibrosis (9,15,60), and a single study showed that these mice have reduced lung compliance and increased elastance by 3 mo of age (28), with evidence of progressively greater deposition of collagen within airways and parenchyma. Whether such changes are associated with altered airway contractility and the specific role of ASM per se have not been examined. In the present study, we compared airway structure and function in wild-type (WT) vs. Cav1 KO mice that were either unsensitized [control (CTL)] or sensitiz...

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“…While patient identifiers are not retained with the samples, medical histories are used to select samples from female non-smokers without other significant chronic airway disease such as asthma. ASM cells were isolated and cultured using previously established procedures [13,[22][23][24][25]. Briefly, smooth muscle from lung tissues was dissected after the epithelium was removed by mild abrasions.…”

Section: Isolation Of Human Asm Cellsmentioning

confidence: 99%

Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle

Sathish¹,

Freeman²,

Long³

et al. 2015

Cell Physiol Biochem

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Aims: Cigarette smoke (CS) in active smokers and second-hand smoke exposure exacerbate respiratory disorders such as asthma and chronic bronchitis. While women are known to experience a more asthmatic response to CS than emphysema in men, there is limited information on the mechanisms of CS-induced airway dysfunction. We hypothesize that CS interferes with a normal (protective) bronchodilatory role of estrogens, thus worsening airway contractility. Methods: We tested effects of cigarette smoke extract (CSE) on 17β-estradiol (E₂) signaling in enzymatically-dissociated bronchial airway smooth muscle (ASM) obtained from lung samples of non-smoking female patients undergoing thoracic surgery. Results: In fura-2 loaded ASM cells, CSE increased intracellular calcium ([Ca²⁺]_i) responses to 10µM histamine. Acute exposure to physiological concentrations of E₂ decreased [Ca²⁺]_i responses. However, in 24h exposed CSE cells, although expression of estrogen receptors was increased, the effect of E₂ on [Ca²⁺]_i was blunted. Acute E₂ exposure also decreased store-operated Ca²⁺ entry and inhibited stromal interaction molecule 1 (STIM1) phosphorylation: effects blunted by CSE. Acute exposure to E₂ increased cAMP, but less so in 24h CSE-exposed cells. 24h CSE exposure increased S-nitrosylation of ERα. Furthermore, 24h CSE-exposed bronchial rings showed increased bronchoconstrictor agonist responses that were not reduced as effectively by E₂ compared to non-CSE controls. Conclusion: These data suggest that CS induces dysregulation of estrogen signaling in ASM, which could contribute to increased airway contractility in women exposed to CS.

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Caveolin-1 and force regulation in porcine airway smooth muscle

Cited by 30 publications

References 78 publications

Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1^−/− mice impair the peristaltic reflex and propulsion

Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1^−/− mice impair the peristaltic reflex and propulsion

Caveolin-1 knockout mice exhibit airway hyperreactivity

Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle

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Caveolin-1 and force regulation in porcine airway smooth muscle

Cited by 30 publications

References 78 publications

Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1−/− mice impair the peristaltic reflex and propulsion

Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1−/− mice impair the peristaltic reflex and propulsion

Caveolin-1 knockout mice exhibit airway hyperreactivity

Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle

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Product

Resources

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Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1^−/− mice impair the peristaltic reflex and propulsion

Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1^−/− mice impair the peristaltic reflex and propulsion