Glucocorticoids inhibited airway hyperresponsiveness through downregulation of CPI-17 in bronchial smooth muscle

Goto, Kumiko; Chiba, Yoshihiko; Sakai, Hiroyasu; Misawa, Miwa

doi:10.1016/j.ejphar.2008.06.021

Cited by 14 publications

(11 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…From this perspective, our data raise the possibility that gestational food restriction in the absence of glucocorticoids causes epigenetic changes in gene expression for calcium-regulating proteins and that glucocorticoids protect against such effects. Although glucocorticoids can produce long-term depression of contractility in cerebral arteries (19) and, over the short term, can inhibit myofilament sensitivity in airway smooth muscle (24) and uterine arteries (69), metyrapone had very little long-term effect on myofilament calcium sensitivity in cerebral arteries of MFR offspring (Fig. 2, bottom).…”

Section: Discussionmentioning

confidence: 95%

Maternal food restriction modulates cerebrovascular structure and contractility in adult rat offspring: effects of metyrapone

Durrant

Khorram

Buchholz

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Although the effects of prenatal undernutrition on adult cardiovascular health have been well studied, its effects on the cerebrovascular structure and function remain unknown. We used a pair-fed rat model of 50% caloric restriction from day 11 of gestation to term, with ad libitum feeding after birth. We validated that maternal food restriction (MFR) stress is mediated by glucocorticoids by administering metyrapone, a corticosterone synthesis inhibitor, to MFR mothers at day 11 of gestation. At age 8 mo, offspring from Control, MFR, and MFR + Metyrapone groups were killed, and middle cerebral artery (MCA) segments were studied using vessel-bath myography and confocal microscopy. Colocalization of smooth muscle α-actin (SMαA) with nonmuscle (NM), SM1 and SM2 myosin heavy-chain (MHC) isoforms was used to assess smooth muscle phenotype. Our results indicate that artery stiffness and wall thickness were increased, pressure-evoked myogenic reactivity was depressed, and myofilament Ca(2+) sensitivity was decreased in offspring of MFR compared with Control rats. MCA from MFR offspring exhibited a significantly greater SMαA/NM colocalization, suggesting that the smooth muscle cells had been altered toward a noncontractile phenotype. MET significantly reversed the effects of MFR on stiffness but not myogenic reactivity, lowered SMαA/NM colocalization, and increased SMαA/SM2 colocalization. Together, our data suggest that MFR alters cerebrovascular contractility via both glucocorticoid-dependent and glucocorticoid-independent mechanisms.

show abstract

Section: Discussionmentioning

confidence: 95%

Maternal food restriction modulates cerebrovascular structure and contractility in adult rat offspring: effects of metyrapone

Durrant

Khorram

Buchholz

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

“…The ACh-induced activation of CPI-17 was also significantly inhibited by glucocorticoids. Glucocorticoids prevented the augmented ACh-induced MLC phosphorylation observed in rat AHR (80). Therefore, glucocorticoids may inhibit AHR through inhibition of CPI-17 overexpression and activation (80).…”

Section: Involvement Of Cpi-17 In Smooth Muscle Contractionmentioning

confidence: 96%

Mechanisms underlying the pathogenesis of hyper-contractility of bronchial smooth muscle in allergic asthma

Sakai

Suto

Kai

et al. 2017

J. Smooth Muscle Res.

Self Cite

View full text Add to dashboard Cite

Airway hyperresponsiveness (AHR) and inflammation are key pathophysiological features of asthma. Enhanced contraction of bronchial smooth muscle (BSM) is one of the causes of the AHR. It is thus important for development of asthma therapy to understand the change in the contractile signaling of airway smooth muscle cells associated with the AHR. In addition to the Ca2+-mediated phosphorylation of myosin light chain (MLC), contractile agonists also enhance MLC phosphorylation level, Ca2+-independently, by inactivating MLC phosphatase (MLCP), called Ca2+ sensitization of contraction, in smooth muscle cells including airways. To date, involvements of RhoA/ROCKs and PKC/Ppp1r14a (also called as CPI-17) pathways in the Ca2+ sensitization have been identified. Our previous studies revealed that the agonist-induced Ca2+ sensitization of contraction is markedly augmented in BSMs of animal models of allergen-induced AHR. In BSMs of these animal models, the expression of RhoA and CPI-17 proteins were significantly increased, indicating that both the Ca2+ sensitizing pathways are augmented. Interestingly, incubation of BSM cells with asthma-associated cytokines, such as interleukin-13 (IL-13), IL-17, and tumor necrosis factor-α (TNF-α), caused up-regulations of RhoA and CPI-17 in BSM cells of naive animals and cultured human BSM cells. In addition to the transcription factors such as STAT6 and NF-κB activated by these inflammatory cytokines, an involvement of down-regulation of miR-133a, a microRNA that negatively regulates RhoA translation, has also been suggested in the IL-13- and IL-17-induced up-regulation of RhoA. Thus, the Ca2+ sensitizing pathways and the cytokine-mediated signaling including microRNAs in BSMs might be potential targets for treatment of allergic asthma, especially the AHR.

show abstract

“…Taken together, the above observations underscore the critical role played by ASM in regulating its responsiveness to endogenous GCs and thereby the proasthmatic impact of IL-13 on ASM function. In this regard, although the present study did not address the specific mechanism(s) by which endogenous GCs attenuate IL-13-induced changes in ASM contractility, recent reports have identified several potential mechanisms of action of GCs in modulating ASM function, including induced changes in gene expression via transactivation and transrepression mechanisms, inhibition of contractile protein expression and function, altered agoniststimulated intracellular Ca 2ϩ signaling, and other mechanisms (19,20,29,34,41). Moreover, it should be noted that, apart from enabling endogenous GCs to modulate ASM contractility, the presence of an intrinsic 11␤-HSD1-dependent homeostatic mechanism in ASM likely serves to also facilitate other known GC-sensitive actions in ASM, including inhibition of ASM proliferation and prevention of its stimulated release of various cytokines and chemokines (27,38), potentially including cytokines released by IL-13-stimulated ASM cells (25).…”

Section: Discussionmentioning

confidence: 90%

Th2 cytokine-induced upregulation of 11β-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function

Hu¹,

Fatma²,

Cao³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

Glucocorticoids inhibited airway hyperresponsiveness through downregulation of CPI-17 in bronchial smooth muscle

Cited by 14 publications

References 37 publications

Maternal food restriction modulates cerebrovascular structure and contractility in adult rat offspring: effects of metyrapone

Maternal food restriction modulates cerebrovascular structure and contractility in adult rat offspring: effects of metyrapone

Mechanisms underlying the pathogenesis of hyper-contractility of bronchial smooth muscle in allergic asthma

Th2 cytokine-induced upregulation of 11β-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function

Contact Info

Product

Resources

About