Endothelial ET&lt;sub&gt;B&lt;/sub&gt; Limits Vascular Remodelling and Development of Pulmonary Hypertension during Hypoxia

Kelland, NF; BAGNALL, A; Morecroft, Ian; Gulliver-Sloan, FH; Dempsie, Yvonne; Nilsen, Margaret; Yanagisawa, Masashi; MacLean, Margaret R.; Kotelevtsev, Yuri; Webb, David J.

doi:10.1159/000231717

Cited by 18 publications

(18 citation statements)

References 71 publications

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“…3B). It is worth noting that a complete knockout of EdnrB even in specific cells may be deleterious (47). Because EdnrB −/+ mice maintain better cardiac performance under various levels of hypoxia, we argue that a down-regulated level of EDNRB receptor in EdnrB −/+ mice is sufficient for normal functioning, as seen in normoxia (P > 0.05).…”

Section: Discussionmentioning

confidence: 79%

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Stobdan

Zhou

Ao-Ieong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB −/+ heterozygote mice are treated with lower levels of oxygen (O 2 ), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O 2 ) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O 2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB −/+ compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB −/+ mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB −/+ and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.is often referred to as a biosignature, a chemical marker in the atmosphere closely associated with life, and in a complex organism, such as humans, various physiological systems have evolved to maintain an optimal O 2 homeostasis. Arguably, humans living at high altitude (HA) for thousands of years ought to have undergone a significant level of natural selection to adjust to the challenging hypoxic condition. Human adaptation to HA hypoxia, which can be protective to tissues, can potentially be harnessed for better therapeutic modalities for sea-level diseases that involve hypoxia and ischemia in their pathogenesis. Indeed, lessons from such an "experiment in nature" can be derived from HA adaptation and can advance lowaltitude medicine (1). With the advent of newer technology including next-generation sequencing (seq), this idea has recently led to intensive efforts, and a number of publications have appeared on studies of human populations living at HA (2-4). These studies also draw added significance not only to sea-level human diseases but also to more than 140 million people living at an altitude above 2,500 m, where the hypoxic condition presents a major challenge for survival (5). Although a number of laboratory methods that mimic hypoxia adaptation using model organisms (6) have been used as tools to identify causative genetic pathways (7,8), studies in human populations living at different H...

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Section: Discussionmentioning

confidence: 79%

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Stobdan

Zhou

Ao-Ieong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Activation of ET A leads to vasoconstriction, and as a result, ET A antagonists are used in the treatment of PAH due to their vasodilatory properties (54, 55). The role of ET B is less clear; it is believed to regulate the actions following ET A activation, through the release of NO and prostacyclin, and is also thought to restrict the release of ET‐1 from endothelial cells (54, 56). Elevated plasma levels of ET‐1 have been detected in patients with PH (57), correlating with increased vascular resistance and pulmonary arterial pressure (58–60).…”

Section: Discussionmentioning

confidence: 99%

The A _2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease

Karmouty‐Quintana¹,

Zhong

Acero³

et al. 2012

FASEB j.

105

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Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A(2B)R) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A(2B)R or treatment with the A(2B)R antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A(2B)R attenuated vascular remodeling and hypertension in our model. Furthermore, direct A(2B)R activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A(2B)R antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.

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“…In rats, ET B deficiency exacerbates monocrotaline (39) and hypoxia-induced PH (40). Impaired extracellular ET B-mediated NO/prostaglandin 2 release from pulmonary resistance vessels during hypoxia may have contributed to the development of PAH (41). In both the TG animal model and the transfected model with hEC-SOD, there was a significant decrease of vascular remodeling after exposure to hypoxia compared with the WT animal model.…”

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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Endothelial ET<sub>B</sub> Limits Vascular Remodelling and Development of Pulmonary Hypertension during Hypoxia

Cited by 18 publications

References 71 publications

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

The A _2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease

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

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Endothelial ET<sub>B</sub> Limits Vascular Remodelling and Development of Pulmonary Hypertension during Hypoxia

Cited by 18 publications

References 71 publications

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

The A 2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease

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

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The A _2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease