Preferential Expression and Function of Voltage-Gated, O
            <sub>2</sub>
            -Sensitive K
            <sup>+</sup>
            Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Archer, Stephen L.; Wu, Xi-Chen; Thébaud, Bernard; Nsair, Ali; Bonnet, Sébastien; Tyrrell, B.; McMurtry, M. Sean; Hashimoto, Kyoko; Harry, Gwyneth; Michelakis, Evangelos D.

doi:10.1161/01.res.0000137173.42723.fb

Cited by 180 publications

(190 citation statements)

References 59 publications

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“…Several members of the K V channel superfamily, including K V 1.2, K V 1.5, K V 2.1, K V 3.1 and K V 9.3, have been found to be expressed by PASMCs [14][15][16]. Among these, particular attention has been given to K V 1.5 (encoded by the KCNA5 gene), preferentially expressed in the small resistance pulmonary arteries rather than in conduit pulmonary arteries and diminished in PASMC following hypoxia exposure [14,15]. Reduced expression of K V 1.5 is a common denominator of human and experimental PAH suggesting an important role of this channel in the pathogenesis of various forms of PH [16][17][18][19].…”

Section: Potassium Channels In Regulation Of Cell Proliferation and Cmentioning

confidence: 99%

Potassium channels in pulmonary arterial hypertension

et al. 2015

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Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with various origins. All forms of PAH share a common pulmonary arteriopathy characterised by vasoconstriction, remodelling of the pre-capillary pulmonary vessel wall, and in situ thrombosis. Although the pathogenesis of PAH is recognised as a complex and multifactorial process, there is growing evidence that potassium channels dysfunction in pulmonary artery smooth muscle cells is a hallmark of PAH. Besides regulating many physiological functions, reduced potassium channels expression and/or activity have significant effects on PAH establishment and progression. This review describes the molecular mechanisms and physiological consequences of potassium channel modulation. Special emphasis is placed on KCNA5 (Kv1.5) and KCNK3 (TASK1), which are considered to play a central role in determining pulmonary vascular tone and may represent attractive therapeutic targets in the treatment of PAH. @ERSpublications Comprehensive overview of the roles of potassium channels in the pathogenesis of pulmonary arterial hypertension

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Section: Potassium Channels In Regulation Of Cell Proliferation and Cmentioning

confidence: 99%

Potassium channels in pulmonary arterial hypertension

et al. 2015

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“…For example, hypoxic pulmonary vasoconstriction and pulmonary hypertension develop when alveolar PO 2 is 40-60 mm Hg (2,5,13), a value that is substantially higher than that in other organs under conditions of normal oxygenation (14)(15)(16). This implies that there are specific mechanisms within the lung that are responsible for sensing and responding to changes in PO 2 , which are different from those found in other organs and tissues.…”

mentioning

confidence: 99%

Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

Leonard

Howell

Madden

et al. 2008

Am J Respir Crit Care Med

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Rationale: Pulmonary hypertension is a common complication of chronic hypoxic lung diseases and is associated with increased morbidity and reduced survival. The pulmonary vascular changes in response to hypoxia, both structural and functional, are unique to this circulation. Objectives: To identify transcription factor pathways uniquely activated in the lung in response to hypoxia. Methods: After exposure to environmental hypoxia (10% O 2 ) for varying periods (3 h to 2 wk), lungs and systemic organs were isolated from groups of adult male mice. Bioinformatic examination of genes the expression of which changed in the hypoxic lung (assessed using microarray analysis) identified potential lung-selective transcription factors controlling these changes in gene expression. In separate further experiments, lung-selective activation of these candidate transcription factors was tested in hypoxic mice and by comparing hypoxic responses of primary human pulmonary and cardiac microvascular endothelial cells in vitro. Measurements and Main Results: Bioinformatic analysis identified cAMP response element binding (CREB) family members as candidate lung-selective hypoxia-responsive transcription factors. Further in vivo experiments demonstrated activation of CREB and activating transcription factor (ATF)1 and up-regulation of CREB family-responsive genes in the hypoxic lung, but not in other organs. Hypoxia-dependent CREB activation and CREB-responsive gene expression was observed in human primary lung, but not cardiac microvascular endothelial cells. Conclusions: These findings suggest that activation of CREB and AFT1 plays a key role in the lung-specific responses to hypoxia, and that lung microvascular endothelial cells are important, proximal effector cells in the specific responses of the pulmonary circulation to hypoxia.Keywords: hypoxia; cAMP response element binding; pulmonary hypertension; transcription factor binding site Pulmonary hypertension is a common complication of chronic hypoxic lung diseases, which is associated with increased morbidity and reduced survival. Moreover, cor pulmonale is an independent predictor of increased mortality, suggesting that pulmonary hypertension contributes directly to reduced survival (1, 2). The increased pulmonary vascular resistance underlying chronic hypoxic pulmonary hypertension is accompanied by characteristic changes in the blood vessels, which include remodeling and thickening of the walls of precapillary vessels and sustained vasoconstriction (3-8). These long-term structural and functional changes in the pulmonary vessels in response to hypoxia are unique to this circulation, and are not observed in the vasculature of other organs of the body.The important roles of the vascular endothelium in the local control of vascular smooth muscle tone and in modulating changes in the structure of the vessel wall are now well recognized (9). It is also well recognized that endothelial cells from different organs show considerable heterogeneity, and that their roles in the control ...

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“…The most studied model of tonus increase in the pulmonary circulation is the vasoconstriction due to hypoxia. The reduction in alveolar oxygen tension promotes a fast and reversible increase of pulmonary vascular resistance, which starts in less than one minute, quickly reversing with the normalization of oxygenation conditions 6 . The mechanism starting vasoconstriction is the inhibition of many potassium channels, designated by K v , followed by cellular membrane depolarization and entry of calcium through L-type channels.…”

Section: Changes In Pulmonary Vascular Tonus: Pulmonary Vasoconstrictmentioning

confidence: 99%

Hipertensão arterial pulmonar: fisiopatologia, aspectos genéticos e resposta ao uso crônico do sildenafil

Barreto¹,

Franchi²,

Pereira³

et al. 2005

Arq. Bras. Cardiol.

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Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Cited by 180 publications

References 59 publications

Potassium channels in pulmonary arterial hypertension

Potassium channels in pulmonary arterial hypertension

Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

Hipertensão arterial pulmonar: fisiopatologia, aspectos genéticos e resposta ao uso crônico do sildenafil

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Preferential Expression and Function of Voltage-Gated, O 2 -Sensitive K + Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction

Cited by 180 publications

References 59 publications

Potassium channels in pulmonary arterial hypertension

Potassium channels in pulmonary arterial hypertension

Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

Hipertensão arterial pulmonar: fisiopatologia, aspectos genéticos e resposta ao uso crônico do sildenafil

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Preferential Expression and Function of Voltage-Gated, O ₂ -Sensitive K ⁺ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction