Increased endothelin receptor gene expression in hypoxic rat lung

Li, H.; Elton, Terry S.; Chen, Y. F.; Oparil, Suzanne

doi:10.1152/ajplung.1994.266.5.l553

Cited by 73 publications

(76 citation statements)

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“…The shunted piglets presented with an overexpressed ET B receptor. This has also been observed in rats with hypoxic pulmonary hypertension 23 and in patients with thromboembolic pulmonary hypertension. 24 The ET B receptor has been shown to be involved in the clearance of circulating ET-1, the modulation of ET-1 synthesis through a negative feedback, and the release of endothelium-derived vasodilators 2 but may also contribute to ET-1-induced remodeling.…”

Section: ј-Agtctggcttatatccaacacttcg-3јsupporting

confidence: 62%

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

et al. 2003

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Background-The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy. Methods and Results-Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET B receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET A receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan. Conclusions-Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan. (Circulation. 2003;107:1329-1335.)

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Section: ј-Agtctggcttatatccaacacttcg-3јsupporting

confidence: 62%

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

et al. 2003

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“…Endothelin-1 appears to play a role in hypoxia-induced pulmonary hypertension. An increased expression of endothelin-1 and the endothelin A receptor has been reported in rats exposed to a FI,O 2 of 0.1 for 48 h [21], with addition of an overexpression of the endothelin B receptor after increase of the duration of the hypoxic exposure to 4 weeks [22]. Both selective endothelin A …”

Section: Discussionmentioning

confidence: 91%

Pulmonary artery pressure limits exercise capacity at high altitude

Naeije¹,

Huez²,

Lamotte³

et al. 2010

Eur Respir J

102

108

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Altitude exposure is associated with decreased exercise capacity and increased pulmonary vascular resistance (PVR).Echocardiographic measurements of pulmonary haemodynamics and a cardiopulmonary exercise test were performed in 13 healthy subjects at sea level, in normoxia and during acute hypoxic breathing (1 h, 12% oxygen in nitrogen), and in 22 healthy subjects after acclimatisation to an altitude of 5,050 m. The measurements were obtained after randomisation, double-blinded to the intake of placebo or the endothelin A receptor blocker sitaxsentan (100 mg?day -1 for 7 days). Blood and urine were sampled for renal function measurements. Normobaric as well as hypobaric hypoxia increased PVR and decreased maximum workload and oxygen uptake (V9O 2 ,max). Sitaxsentan decreased PVR in acute and chronic hypoxia (both p,0.001), and partly restored V9O 2 ,max, by 30 % in acute hypoxia (p,0.001) and 10% in chronic hypoxia (p,0.05). Sitaxsentan-induced changes in PVR and V9O 2 ,max were correlated (p50.01). Hypoxia decreased glomerular filtration rate and free water clearance, and increased fractional sodium excretion. These indices of renal function were unaffected by sitaxsentan intake.Selective endothelin A receptor blockade with sitaxsentan improves mild pulmonary hypertension and restores exercise capacity without adverse effects on renal function in hypoxic normal subjects.

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“…Preproendothelin-1 has been more extensively studied and documented in vascular endothelial cells, as well as smooth muscle cells, heart, lung, kidney, brain, and skin (27)(28)(29). Increased endothelin expression has been reported in pulmonary hyper- tension (36), myocardial ischemia (37), and congestive heart failure (38). These are conditions associated with elevated elastase activity where it would be advantageous to assess the possible protective effects of very high levels of elafin expression.…”

Section: Discussionmentioning

confidence: 99%

Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis

Zaidi¹,

Hui²,

Cheah³

et al. 1999

J. Clin. Invest.

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Serine elastases degrade elastin, stimulate vascular smooth muscle cell migration and proliferation, and are associated with myocardial damage. To evaluate the impact of elastase inhibition on cardiovascular development and disease, transgenic mice were created in which the mouse preproendothelin-1 promoter was used to target elafin overexpression to the cardiovascular system. To distinguish the transgene from endogenous elafin, constructs were made incorporating a FLAG sequence; the COOH-terminus FLAG-tagged elafin construct produced a stable, functionally active gene product and was used to create transgenic mice. Consistent with endothelin expression, abundant elafin mRNA was observed in transgenic F1 embryos (embryonic day 13.5) and in adult transgenic mice heart, trachea, aorta, kidney, lung, and skin, but not in liver, spleen, and intestine. Functional activity of the transgene was confirmed by heightened myocardial elastase inhibitory activity. No tissue abnormalities were detected by light microscopy or elastin content. However, injection of 10 plaque-forming units (PFU) of encephalomyocarditis virus resulted in death within 11 days in 10 out of 12 nontransgenic mice compared with one out of nine transgenic littermates. This reduced mortality was associated with better cardiac function and less myocardial inflammatory damage. Thus, elafin expression may confer a protective advantage in myocarditis and other inflammatory diseases.

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Increased endothelin receptor gene expression in hypoxic rat lung

Cited by 73 publications

References 0 publications

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

Pulmonary artery pressure limits exercise capacity at high altitude

Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis

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