Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension

Stelzner, Thomas J.; O'Brien, Richard F.; Yanagisawa, Masashi; Sakurai, Tadashi; Sato, Koichi; Webb, Sally A.; Zamora, M.; McMurtry, Ivan F.; Fisher, Jennifer

doi:10.1152/ajplung.1992.262.5.l614

Cited by 84 publications

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“…It is well known that pulmonary vascular remodelling occurs in various kinds of experimental PH, induced by hypoxia [14±16, 23±25], monocrotaline [26], hyperperfusion [27], and in fawn-hooded rats [28,29]. In addition, postobstructive pulmonary vasculopathy (POPV) induced by chronic, unilateral pulmonary artery ligation has been shown to cause vascular remodelling [30±32].…”

Section: Discussionmentioning

confidence: 99%

Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension

Kim¹,

Yung²,

Marsh³

et al. 2000

Eur Respir J

124

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It is well known that endothelin (ET)-1 mediates vascular remodelling in various kinds of clinical and experimental pulmonary hypertension. The aim of this study was to investigate whether ET-1 is associated with the development of pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.Pulmonary hypertension was induced in 10 mongrel dogs by repeated embolization with ceramic beads. In five of the dogs, bosentan, a nonselective ET receptor antagonist, was administered throughout the study. Haemodynamic measurements and plasma ET-1 assays were performed every 2 months. Eight months after initial embolization, computer-assisted morphometry and immunohistochemistry were performed on the lung tissue including that from three control dogs.Pulmonary arterial pressure and pulmonary vascular resistance were increased in all embolized dogs, compared to baseline. In nontreated embolized dogs, plasma ET-1 concentration and pulmonary arterial wall thickness were increased compared to control animals, and ET-1 immunoreactivity was detected in thickened pulmonary arteries. In bosentan treated dogs, pulmonary arterial walls were not significantly thickened.Pulmonary vascular remodelling, associated with elevated plasma endothelin-1 levels and positive endothelin-1 immunoreactivity in lung tissue is attenuated by the endothelin receptor antagonist, bosentan. These findings suggest that endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Eur Respir J 2000; 15: 640±648. There is increasing evidence that remodelling occurs in the pulmonary vascular bed of patients with chronic thromboembolic pulmonary hypertension (CTEPH) and may contribute to the progression of the disease [1±5]. The mechanisms responsible for this remodelling are, however, poorly understood.Endothelin (ET)-1 is a potent endogenous vasoconstrictor in the pulmonary circulation and also a growth factor in the pulmonary vasculature [6]. These constrictor and proliferative responses are mainly mediated by ET A receptors [7,8], and blocked by selective and nonselective antagonists [9,10]. Previous studies have shown that ET-1 is upregulated in the lungs of primary and secondary pulmonary hypertensive patients [11±13], and ET antagonists have been shown to attenuate the development of pulmonary vascular remodelling and pulmonary hypertension (PH) in various animal models [14±16]. In the CTEPH, however, the role of ET-1 is still unclear.Using a canine model of thromboembolic PH, which the authors have previously developed [17,18], this study was performed to: 1) see whether pulmonary vascular remodelling occurs in a canine model of chronic embolic pulmonary hypertension (CEPH); 2) examine the changes of ET-1 in association with the development of CEPH; and 3) evaluate the effects of bosentan, a nonselective ET receptor antagonist, on pulmonary vascular remodelling in CEPH. Material and methods Study animalsA total of 10 mongrel dogs (body weight 19±23 kg) were used ...

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Section: Discussionmentioning

confidence: 99%

Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension

Kim¹,

Yung²,

Marsh³

et al. 2000

Eur Respir J

124

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“…Changes in lung ET-1 are therefore not the consequence but probably a cause of pulmonary hypertension [78].…”

Section: Pulmonary Hypertensionmentioning

confidence: 96%

“…Hypoxic stress is associated with increases in the plasma ET-1 level, and in ET-1 content and the expression of ET-1 mRNA of the lung, suggesting that the lungs are a source of plasma ET-1 and may play a role in the development of hypoxia-induced pulmonary hypertension [77]. In addition, the rat model of idiopathic pulmonary hypertension named fawn-hooded rats shows increased ET-1 content and ET-1 mRNA expression in the lung prior to the development of pulmonary hypertension.Changes in lung ET-1 are therefore not the consequence but probably a cause of pulmonary hypertension [78].In monocrotaline-induced pulmonary hypertension in rats, Miyauchi et al [79] showed an increase in plasma ET-1 associated with an increase in the expression of ET-1 mRNA in the kidneys and hearts. On the contrary, the expression of ET-1 mRNA and ET-1 content in the lungs decreased gradually as pulmonary hypertension developed, suggesting that the lungs are not the source of plasma ET-1.…”

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confidence: 99%

Recent Advances in Endothelin Research on Cardiovascular and Endocrine Systems.

Naruse¹,

Naruse²,

Demura³

1994

Endocr J

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IntroductionSince the quite exciting discovery in 1988 of endothelin (ET) in the culture medium of aortic endothelial cells by Yanagisawa and coworkers [1], evidence has accumulated to support its important roles in the regulation of blood pressure and body fluid homeostasis and its pathophysiological significance in various cardiovascular diseases. The discovery of ET and the opponent substances including nitric oxide [2] and natriuretic peptides [3] during the last decade was epoch-making in the field of "Cardiovascular Endocrinology". Because of its impressive potency and the long duration of its pressor action [1], the roles of ET in the regulation of cardiovascular homeostasis have been extensively studied.However, the co-expression or close localization of ET and its receptors in various tissues other than the vascular vessels suggest non-vascular roles of ET [4][5][6]. In the present review, we firstly integrate the information relevant to its physiological role in blood pressure regulation and possible pathogenic role in hypertension.We secondarily focus on the possible roles of ET in the endocrine system, especially in the pituitary and adrenal.Substantial review articles on ET in the kidney [7,8], ET and the heart [9], the growth regulating properties of ET [10], and ET in bronchial diseases [11, 12] have been published. Structure of ET and ET ReceptorThe molecular and biochemical aspects of ET family peptides and ET receptors have been reviewed by Masaki and Yanagisawa [13] and others [14][15][16]. We here describe the fundamentals. ET PeptidesThe ET molecule consists of 21 amino acid residues with two intramolecular disulfide bonds between cystein residues at 1 and 15 and 3 and 11, respectively. The ring structure and the hydrophobic amino acid residues at the C-terminus are indispensable to its full biological activities. There are three distinct isof orms of ET: ET-1, . The difference in the amino acid sequence is seen in the ring structure, while they share the same sequence in the linear C-terminal portion. Interspecies differences are minimal [13][14][15][16]. Interestingly, the amino acid sequence of a family of rare snake venoms, the sarafotoxins, is very similar to the sequence of ET [16], composing the ET-sarafotoxin family and suggesting the importance of the peptide in evolution.PreproET-1, the precursor of the peptide, is synthesized through the gene transcription and translation. Expression of the preproET-1 mRNA in the endothelial cells is stimulated by various humoral and physical factors: thrombin, TGF-f3, interleukin-1, TNF-a, angiotensin II (Ang II), vasopressin, and shear stress (for review see [13][14][15] produced.In addition, the existence of ET was also shown by immunoassay in a variety of tissues other than the vascular endothelium [22]. The ET-1 content is the highest in the posterior pituitary and the lung followed by the anterior pituitary, brain, and adrenal gland. The ET-3 content is highest in the posterior and anterior pituitaries.The ET-1 content is significantly hi...

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“…Chronic hypoxia increases ROS levels and impairs endothelial NO-dependent relaxation in mouse pulmonary arteries (29,30). The role of endothelin-1, its vasoconstrictor effect under hypoxic conditions and its role in progression of the PH process have been studied previously (31). Plasma concentration of endothelin-1 correlates with severity of PAH in both animal models (32)(33)(34) and patients (35).…”

Section: E C -S O D a N D T R E A T M E N T O F P U L M O N A R Y H Ymentioning

confidence: 99%

Extracellular Superoxide Dismutase Overexpression Can Reverse the Course of Hypoxia-Induced Pulmonary Hypertension

Ahmed

Zhang

Codipilly

et al. 2011

Mol Med

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Hypoxia leads to free radical production, which has a pivotal role in the pathophysiology of pulmonary hypertension (PH). We hypothesized that treatment with extracellular superoxide dismutase (EC-SOD) could ameliorate the development of PH induced by hypoxia. In vitro studies using pulmonary microvascular endothelial cells showed that cells transfected with EC-SOD had significantly less accumulation of xanthine oxidase and reactive oxygen species than nontransfected cells after hypoxia exposure for 24 h. To study the prophylactic role of EC-SOD, adult male wild-type (WT) and transgenic (TG) mice, with lung-specific overexpression of human EC-SOD (hEC-SOD), were exposed to fraction of inspired oxygen (FiO 2 ) 10% for 10 d. After exposure, right ventricular systolic pressure (RVSP), right ventricular mass (RV/S + LV), pulmonary vascular wall thickness (PVWT) and pulmonary artery contraction/relaxation were assessed. TG mice were protected against PH compared with WT mice with significantly lower RVSP (23.9 ± 1.24 versus 47.2 ± 3.4), RV/S + LV (0.287 ± 0.015 versus 0.335 ± 0.022) and vascular remodeling, indicated by PVWT (14.324 ± 1.107 versus 18.885 ± 1.529). Functional studies using pulmonary arteries isolated from mice indicated that EC-SOD prevents hypoxia-mediated attenuation of nitric oxide-induced relaxation. Therapeutic potential was assessed by exposing WT mice to FiO 2 10% for 10 d. Half of the group was transfected with plasmid containing cDNA encoding human EC-SOD. The remaining animals were transfected with empty vector. Both groups were exposed to FiO 2 10% for a further 10 d. Transfected mice had significantly reduced RVSP (18.97 ± 1.12 versus 41.3 ± 1.5), RV/S + LV (0.293 ± 0.012 versus 0.372 ± 0.014) and PVWT (12.51 ± 0.72 versus 18.98 ± 1.24). On the basis of these findings, we concluded that overexpression of EC-SOD prevents the development of PH and ameliorates established PH.

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Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension

Cited by 84 publications

References 0 publications

Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension

Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension

Recent Advances in Endothelin Research on Cardiovascular and Endocrine Systems.

Extracellular Superoxide Dismutase Overexpression Can Reverse the Course of Hypoxia-Induced Pulmonary Hypertension

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