Transforming growth factor-β downregulates sGC subunit expression in pulmonary artery smooth muscle cells via MEK and ERK signaling

Du, Lili; Roberts, Jesse D.

doi:10.1152/ajplung.00319.2018

Cited by 9 publications

(7 citation statements)

References 100 publications

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“…1C). The specificity of the anti-sGC␣1 antibody used here and in subsequent work was shown previously (16). It is interesting to note that the anti-sGC␣1 antibody reactivity was also detected in the nuclear region of the fibroblasts.…”

Section: Resultssupporting

confidence: 79%

“…We next tested whether IL-1␤ decreases sGC␣1 gene expression in the mouse pup lung. As before (16), a single band with a molecular weight consistent with the sGC␣1 protein subunit was detected in control mouse pup lung proteins using an anti-sGC␣1 antibody and immunoblotting (Fig. 7).…”

Section: L26supporting

confidence: 69%

“…In support of this notion, we also observed that heterologous expression of TAK1 also decreased sGC␣1 mRNA levels in rat pulmonary artery SMC and in HEK293T cells (data not shown). Though in the smooth muscle cells, TAK1 did not mediate the decrease in sGC␣1 mRNA expression that is caused by TGF␤ (16).…”

Section: L25mentioning

confidence: 78%

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IL-1β dysregulates cGMP signaling in the newborn lung

Zhong

Bry

Roberts

2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cyclic guanosine monophosphate (cGMP) signaling is an important regulator of newborn lung function and development. Although cGMP signaling is decreased in many models of newborn lung injury, the mechanisms are poorly understood. We determined how IL-1β regulates the expression of the α1-subunit of soluble guanylate cyclase (sGCα1), a prime effector of pulmonary cGMP signaling. Physiologic levels of IL-1β were discovered to rapidly decrease sGCα1 mRNA expression in a human fetal lung fibroblast cell line (IMR-90 cells) and protein levels in primary mouse pup lung fibroblasts. This sGCα1 expression inhibition appeared to be at a transcriptional level; IL-1β treatment did not alter sGCα1 mRNA stability, although it reduced sGCα1 promoter activity. Transforming growth factor-β (TGFβ)-activated kinase-1 (TAK1) was determined to be required for IL-1β’s regulation of sGCα1 expression; TAK1 knockdown protected sGCα1 mRNA expression in IL-1β-treated IMR-90 cells. Moreover, heterologously expressed TAK1 was sufficient to decrease sGCα1 mRNA levels in those cells. Nuclear factor-κB (NF-κB) signaling played a critical role in the IL-1β-TAK1-sGCα1 regulatory pathway; chromatin immunoprecipitation studies demonstrated enhanced activated NF-κB subunit (RelA) binding to the sGCα1 promoter after IL-1β treatment unless treated with an IκB kinase-2 inhibitor. Also, this NF-κB signaling inhibition protected sGCα1 expression in IL-1β-treated fibroblasts. Lastly, using transgenic mice in which active IL-1β was conditionally expressed in lung epithelial cells, we established that IL-1β expression is sufficient to stimulate TAK1 and decrease sGCα1 protein expression in the newborn lung. Together these results detail the role and mechanisms by which IL-1β inhibits cGMP signaling in the newborn lung.

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Section: Resultssupporting

confidence: 79%

Section: L26supporting

confidence: 69%

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IL-1β dysregulates cGMP signaling in the newborn lung

Zhong

Bry

Roberts

2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Endothelium-dependent vasodilatory responses were most impaired in the small arteries and large arterioles in fa/fa-Veh group rats. Notably, using direct visualization of the renal vasculature we showed that smooth muscle dysfunction was also evident in the smaller vessels of fa/fa-Veh group rats, most likely due to upregulation of TGF-b1, oxidative stress, and downregulation of soluble guanylyl cyclase in the renal vasculature (Du and Roberts, 2019), and this was prevented by concurrent treatment with LIRA. NO and or EDHF-mediated dilation in both conduit and resistance vessels was maintained by chronic LIRA treatment in the fa/fa rats.…”

Section: Discussionmentioning

confidence: 86%

Liraglutide Improves Renal Endothelial Function in Obese Zucker Rats on a High-Salt Diet

Sukumaran¹,

Tsuchimochi²,

Sonobe³

et al. 2019

J Pharmacol Exp Ther

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Metabolic syndrome is a common risk factor in chronic kidney disease. We investigated whether liraglutide [(LIRA), a glucagonlike peptide-1 receptor (GLP-1R) agonist] treatment improved renal vascular function and renal remodeling in male Zucker rats on a high-salt diet (6% NaCl). Zucker lean (1/1) and obese (fa/fa) rats (8 weeks old) were treated with vehicle or LIRA (0.1 mg/kg per day) for 8 weeks on a high-salt diet. The glomerular filtration rate (GFR) was measured at 0 and 8 weeks using the fluorescein isothiocyanate/sinistrin method in conscious rats. We used X-ray microangiography to measure renal arterial vessel diameter (70-350 mm) and vessel number in vivo in anesthetized rats. Renal protein expression levels of nitrotyrosine, CD-68, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), transforming growth factor-b1, cyclooxygenase-2, and GLP-1R were assessed by western blotting. Renal gene expressions were determined by real-time polymerase chain reaction. In contrast to vehicletreated rats, fa/fa-LIRA rats improved GFR, nitric oxide (NO)mediated vasodilation in response to acetylcholine and sodium nitroprusside in small arterial vessels (,200 mm diameter). LIRA treatment increased vessel responsivity to NO donors in comparison with vehicle treatment. Increases in the expressions of proinflammatory, profibrotic, and oxidative stress related genes in fa/fa rats relative to 1/1 were unaltered by LIRA, other than a trend toward attenuation of VCAM-1 gene expression. However, LIRA treatment increased protein expressions of eNOS (P 5 0.014) and VEGF (P 5 0.063), while reducing glomerular macrophage infiltration in comparison with vehicle-treated fa/fa rats. Low-dose LIRA treatment improved renal vascular function through amelioration of vascular dysfunction and improved NO-mediated dilation of small intrarenal arteries and arterioles and a reduction in renal inflammation. Some of the findings from this study were part of an oral presentation entitled "Liraglutide treatment improves renal vascular function in Zucker rats as visualized by microangiography" in a symposium at the American Society of Nephrology (Kidney Week) meeting, October 30 to November 5,

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“…In addition, decreased expression of the sGC enzyme has been observed in alveolar and bronchial epithelial cells and in airway smooth muscle cells in COPD patients and smokers (Glynos et al, 2013;Weissmann et al, 2014), as well as in asthmatic patients and animal models of asthma (Papapetropoulos et al, 2006;London et al, 2018). The underlying mechanism is not well understood but recently, it has been shown that the expression of the α1 subunit of sGC is downregulated by TGF-β in pulmonary artery smooth muscle cells via MEK and ERK signaling (Du and Roberts, 2019) and IL-1β in perinatal lung fibroblasts via TAK1 and NF-κB signaling (Zhong et al, 2020) and both inflammatory mediators are increased in COPD and asthma disease so they FIGURE 3 | Schematic view of T2 eosinophilic airway inflammation in the pathophysiology of asthma. Allergens or epithelial damage activates dendritic cells that secrete cytokines, such as IL-4, leading to Th2 differentiation.…”

Section: Role Of Nitric Oxide System In Bronchial Epithelium Of Asthma and Copd Patientsmentioning

confidence: 99%

Nitric Oxide System and Bronchial Epithelium: More Than a Barrier

et al. 2021

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Airway epithelium forms a physical barrier that protects the lung from the entrance of inhaled allergens, irritants, or microorganisms. This epithelial structure is maintained by tight junctions, adherens junctions and desmosomes that prevent the diffusion of soluble mediators or proteins between apical and basolateral cell surfaces. This apical junctional complex also participates in several signaling pathways involved in gene expression, cell proliferation and cell differentiation. In addition, the airway epithelium can produce chemokines and cytokines that trigger the activation of the immune response. Disruption of this complex by some inflammatory, profibrotic, and carcinogens agents can provoke epithelial barrier dysfunction that not only contributes to an increase of viral and bacterial infection, but also alters the normal function of epithelial cells provoking several lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or lung cancer, among others. While nitric oxide (NO) molecular pathway has been linked with endothelial function, less is known about the role of the NO system on the bronchial epithelium and airway epithelial cells function in physiological and different pathologic scenarios. Several data indicate that the fraction of exhaled nitric oxide (FENO) is altered in lung diseases such as asthma, COPD, lung fibrosis, and cancer among others, and that reactive oxygen species mediate uncoupling NO to promote the increase of peroxynitrite levels, thus inducing bronchial epithelial barrier dysfunction. Furthermore, iNOS and the intracellular pathway sGC-cGMP-PKG are dysregulated in bronchial epithelial cells from patients with lung inflammation, fibrosis, and malignancies which represents an attractive drug molecular target. In this review we describe in detail current knowledge of the effect of NOS-NO-GC-cGMP-PKG pathway activation and disruption in bronchial epithelial cells barrier integrity and its contribution in different lung diseases, focusing on bronchial epithelial cell permeability, inflammation, transformation, migration, apoptosis/necrosis, and proliferation, as well as the specific NO molecular pathways involved.

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Transforming growth factor-β downregulates sGC subunit expression in pulmonary artery smooth muscle cells via MEK and ERK signaling

Cited by 9 publications

References 100 publications

IL-1β dysregulates cGMP signaling in the newborn lung

IL-1β dysregulates cGMP signaling in the newborn lung

Liraglutide Improves Renal Endothelial Function in Obese Zucker Rats on a High-Salt Diet

Nitric Oxide System and Bronchial Epithelium: More Than a Barrier

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