Endothelin-1 receptor antagonists prevent the development of pulmonary emphysema in rats

Chen, Yun-Xia; Hanaoka, Masayuki; Droma, Yunden; Chen, P.; Voelkel, N. F.; Kubo, Keishi

doi:10.1183/09031936.00003909

Cited by 60 publications

(40 citation statements)

References 36 publications

(44 reference statements)

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“…The CSE-induced emphysema model used in the present study has been well established in both rodents and reported in several previous studies (16 -19). Intraperitoneal CSE injection caused enlargement of the alveolar air spaces in rats by 35% (17,18) and this model was also replicated in mice (16,19). The mechanism in this novel animal emphysema model is not completely known but thought to be involved with an autoimmune mechanism in alveolar septal cell destruction (20,21).…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Demethylation Treatment on Cigarette Smoke Extract–Induced Mouse Emphysema Model

et al. 2013

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Abstract. In the present study, we explored the effects of demethylation in a cigarette smoke extract (CSE)-induced mouse emphysema model. Animals were randomly assigned to the control group, CSE group, 5-aza-2′-deoxycytidine (AZA) group, and CSE+AZA group (n = 10 per group). The mitochondrial transcription factor A (mtTFA) promoter methylation increased over 4-fold in the CSE group compared with the control group, which was reversed by AZA. The mtTFA and the cytochrome c oxidase subunit II (COX II) mRNA and protein levels were decreased approximately 3-fold in the CSE group compared with the control group, which was largely restored by AZA. Histological analysis showed that the CSE group exhibited emphysema compared with the control, which was alleviated by AZA. In addition, CSE significantly induced lung cell apoptosis and decreased lung function and lung mitochondrial COX activity, which was mostly restored by AZA. In conclusion, we for the first time provide evidence that demethylation therapy with AZA can effectively improve emphysema, lung function, lung cell apoptosis, and lung mitochondrial COX activity in a CSE-induced mouse emphysema model, which adds fresh insight into the therapeutic potential of demethylating agents in the prevention and treatment of cigarette smokeinduced emphysema.

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Section: Discussionmentioning

confidence: 99%

Protective Effect of Demethylation Treatment on Cigarette Smoke Extract–Induced Mouse Emphysema Model

et al. 2013

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“…Arachidonic acid is then converted into thromboxane A 2 (TXA 2 ) by the action of cyclooxygenase and into leukotrienes by lipoxygenase [107]. AngII can also directly increase the release of ET-1 which can act synergistically by producing vasoconstrictive and bronchoconstrictive effects, inducing the expression of adhesion molecules, oxidative stress, stimulating the release of cytokines and the production of proteases from macrophages (MMP-9) and PMN (elastase) [108][109][110][111][112][113][114][115][116]. An in vivo study showed AngII and its receptor AT 1 R to significantly increase the bronchial hyperresponsiveness and the eosinophilic accumulation in the airways after antigen inhalation, an effect that was attenuated by candesartan [117].…”

Section: Angii Bronchial Hyperresponsiveness and Airway Remodelingmentioning

confidence: 99%

Local Renin-Angiotensin II Systems, Angiotensin-Converting Enzyme and its Homologue ACE2: Their Potential Role in the Pathogenesis of Chronic Obstructive Pulmonary Diseases, Pulmonary Hypertension and Acute Respiratory Distress Syndrome

Kaparianos¹,

Argyropoulou²

2011

CMC

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Renin-angiotensin II-aldosterone axis has long been known as a regulator of blood pressure and fluid homeostasis. Yet, local renin-angiotensin II systems have been discovered and novel actions of angiotensin II (AngII) have emerged among which its ability to act as a immunomodulator and profibrotic molecule. The enzyme responsible for its synthesis, Angiotensin-converting-enzyme (ACE), is present in high concentrations in lung tissue. In the present paper, we review data from studies of the past decade that implicate AngII and functional polymorphisms of the ACE gene that increase ACE activity with increased susceptibility for asthma and chronic obstructive pulmonary disease (COPD) and for pulmonary hypertension. Moreover, drugs that inhibit the synthesis of AngII (ACE inhibitors) or that antagonize its actions on its receptors (Angiotensin II receptor blockers -ARBs) have been shown to provide beneficial effects. Another recent discovery reviewed is the presence of a homologue of ACE, ACE2, which cleaves a single amino acid from AngII and forms a heptapeptide with vasodilatory actions, Ang 1-7. The balance between ACE and ACE2 is crucial for controlling AngII levels. ACE and ACE2 also appear to modify the severity of Acute Respiratory Distress Syndrome (ARDS), with ACE2 playing a protective role. Finally, mention is made to the recent discovery of ACE2 as a receptor for the SARS Corona Virus.

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“…In a separate series of experiments, animals were subjected to normoxia (room air) or hypoxia [inspired O 2 fraction (FIO 2 ) ϭ 10%] for 24 h. In these experiments, rats were injected with BQ-123 (1 mg/kg ip) or an equal volume of saline 15 min before being placed in the hypoxic chamber. Because of the short half-life of circulating BQ-123 (55), rats were given a second injection of BQ-123 or saline at 10 h. The concentration of drug and route of administration were chosen based on methods described in the literature (12).…”

Section: Methodsmentioning

confidence: 99%

Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle cells by endothelin-1

Pisarcik

Maylor

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pisarcik S, Maylor J, Lu W, Yun X, Undem C, Sylvester JT, Semenza GL, Shimoda LA. Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle cells by endothelin-1. Am J Physiol Lung Cell Mol Physiol 304: L549 -L561, 2013. First published February 15, 2013 doi:10.1152/ajplung.00081.2012.-Numerous cellular responses to hypoxia are mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1). HIF-1 plays a central role in the pathogenesis of hypoxic pulmonary hypertension. Under certain conditions, HIF-1 may utilize feedforward mechanisms to amplify its activity. Since hypoxia increases endothelin-1 (ET-1) levels in the lung, we hypothesized that during moderate, prolonged hypoxia ET-1 might contribute to HIF-1 signaling in pulmonary arterial smooth muscle cells (PASMCs). Primary cultures of rat PASMCs were treated with ET-1 or exposed to moderate, prolonged hypoxia (4% O2 for 60 h). Levels of the oxygen-sensitive HIF-1␣ subunit and expression of HIF target genes were increased in both hypoxic cells and cells treated with ET-1. Both hypoxia and ET-1 also increased HIF-1␣ mRNA expression and decreased mRNA and protein expression of prolyl hydroxylase 2 (PHD2), which is the protein responsible for targeting HIF-1␣ for O2-dependent degradation. The induction of HIF-1␣ by moderate, prolonged hypoxia was blocked by BQ-123, an antagonist of ET-1 receptor subtype A. The effects of ET-1 were mediated by increased intracellular calcium, generation of reactive oxygen species, and ERK1/2 activation. Neither ET-1 nor moderate hypoxia induced the expression of HIF-1␣ or HIF target genes in aortic smooth muscle cells. These results suggest that ET-1 induces a PASMC-specific increase in HIF-1␣ levels by upregulation of HIF-1␣ synthesis and downregulation of PHD2-mediated degradation, thereby amplifying the induction of HIF-1␣ in PASMCs during moderate, prolonged hypoxia. calcium; prolyl hydroxylase; pulmonary hypertension IN A VARIETY OF CHRONIC lung diseases, the pulmonary circulation is exposed to prolonged periods of hypoxia, often resulting in the development of pulmonary hypertension. Numerous studies have described the structural and functional changes that occur in the pulmonary circulation in response to chronic hypoxia (60). Structural remodeling, characterized by pulmonary arterial smooth muscle cell (PASMC) proliferation, intimal thickening, and extension of muscle into previously nonmuscular arterioles, is commonly observed with pulmonary hypertension (23,40). Changes in the vascular wall are accompanied by active contraction of vessels, evidenced by acute reduction in pulmonary arterial pressure in response to vasodilatory agents (42, 44). These pulmonary vascular changes result, in large part, from altered expression of genes encoding ion channels and transporters that control PASMC ion homeostasis, including increased expression of Na ϩ /H ϩ exchanger isoform 1 (NHE1) and the canonical transient receptor potential (TRPC) family members TRPC1 and TRPC6, as well as reduced levels of mRNA...

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Endothelin-1 receptor antagonists prevent the development of pulmonary emphysema in rats

Cited by 60 publications

References 36 publications

Protective Effect of Demethylation Treatment on Cigarette Smoke Extract–Induced Mouse Emphysema Model

Protective Effect of Demethylation Treatment on Cigarette Smoke Extract–Induced Mouse Emphysema Model

Local Renin-Angiotensin II Systems, Angiotensin-Converting Enzyme and its Homologue ACE2: Their Potential Role in the Pathogenesis of Chronic Obstructive Pulmonary Diseases, Pulmonary Hypertension and Acute Respiratory Distress Syndrome

Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle cells by endothelin-1

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