Heme Oxygenase-2 and Large-Conductance Ca<sup>2+</sup>-activated K<sup>+</sup> Channels

Roth, Markus; Rupp, Markus; Hofmann, Simone; Mittal, Manish; Fuchs, Beate; Sommer, Natascha; Parajuli, Nirmal; Quanz, Karin; Schubert, Dominic; Dony, Eva; Schermuly, Ralph Theo; Ghofrani, Hossein Ardeschir; Sausbier, Ulrike; Rutschmann, Katrin; Wilhelm, Sarah; Seeger, Werner; Ruth, Peter; Grimminger, Friedrich; Sausbier, Matthias; Weißmann, Norbert

doi:10.1164/rccm.200806-848oc

Cited by 38 publications

(45 citation statements)

References 48 publications

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“…The location of the subunits is also vital to channel function. For example, in addition to the plasma membrane, BK Ca channels are also expressed in the mitochondrial membrane of neurons, and this can influence cell excitability (75,90). Unfortunately, our Western immunoblot analysis only measured whole cell protein content and did not provide information regarding subunit cellular location.…”

Section: Discussionmentioning

confidence: 99%

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Blum-Johnston

Thorpe

Wee

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of largeconductance Ca 2ϩ -activated K ϩ (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca 2ϩ . Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca 2ϩ signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (ϳ140 days gestation) and newborn, 10-to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for Ͼ100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca 2ϩ responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 M nitro-L-arginine methyl ester or 10 M 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel ␣1-subunit expression but increased ␤1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. potassium channels; sheep; pulmonary artery; contractility; maturation; hypoxia REGULATION OF SMOOTH MUSCLE tone in pulmonary arteries during development is a delicate balance of vasoconstrictive and vasorelaxant pathways. Endothelial cells play a crucial role in determining the overall level of vasorelaxation (39, 67), and endothelium-dependent relaxation is partially mediated through bradykinin stimulation (31). Bradykinin is a potent vasodilator that is important in the fetal pulmonary circulation, as well as during inflammation, and its relationship to pulmonary hypertension has been explored (5, 31, 83).Endothelial bradykinin receptor activation induces vasorelaxation through modulation of several different intracellular signaling pathways that are largely dependent on a rise of endothelial intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (67). The most widely studied pathway is bradykinin-induced activation of endothelial nitric oxide (NO) synthase (eNOS), an enzyme that generates NO (64). NO acts on nearby smooth muscle cells to cause downstream stimulation of soluble guanylate cyclase (sGC) pathways that leads to vasorelaxation (3,45). Previous studies have shown that regulatio...

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Section: Discussionmentioning

confidence: 99%

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Blum-Johnston

Thorpe

Wee

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…This system offers the advantage of examining the effects of DDAH1 overexpression in HPV without disturbance by the systemic effects exerted by DDAH1. Preparation of the lungs was performed as described previously (18). Mice were deeply anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg body weight), and were anticoagulated with heparin (1,000 U/kg body weight) by intravenous injection.…”

Section: Isolated Ventilated and Perfused Mouse Lungs In The Determinmentioning

confidence: 99%

“…For exposure to chronic hypoxia, mice were kept in normobaric hypoxia (inspiratory O 2 10%) in a ventilated chamber for 28 days, as described elsewhere (18). Right ventricular systolic pressure (RVSP), the degree of muscularization of small pulmonary arteries, and right ventricular hypertrophy (ratio of the right ventricle (RV) and the left ventricle 1 septum [LV + S]) were determined as described previously (18).…”

Section: Isolated Ventilated and Perfused Mouse Lungs In The Determinmentioning

confidence: 99%

“…Right ventricular systolic pressure (RVSP), the degree of muscularization of small pulmonary arteries, and right ventricular hypertrophy (ratio of the right ventricle (RV) and the left ventricle 1 septum [LV + S]) were determined as described previously (18). The mice were anesthetized with an intraperitoneal injection of a combination of ketamine and xylazine (100 mg/kg and 10 mg/kg body weight, respectively).…”

Section: Isolated Ventilated and Perfused Mouse Lungs In The Determinmentioning

confidence: 99%

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Effects of Dimethylarginine Dimethylaminohydrolase–1 Overexpression on the Response of the Pulmonary Vasculature to Hypoxia

Bakr

Pak

Taye

et al. 2013

Am J Respir Cell Mol Biol

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Acute and sustained hypoxic pulmonary vasoconstriction (HPV), as well as chronic pulmonary hypertension (PH), is modulated by nitric oxide (NO). NO synthesis can be decreased by asymmetric dimethylarginine (ADMA), which is degraded by dimethylarginine dimethylaminohydrolase-1 (DDAH1). We investigated the effects of DDAH1 overexpression (DDAH1 tg ) on HPV and chronic hypoxia-induced PH. HPV was measured during acute (10 min) and sustained (3 h) hypoxia in isolated mouse lungs. Chronic PH was induced by the exposure of mice to 4 weeks of hypoxia. ADMA and cyclic 39,59-guanosine monophosphate (cGMP) were determined by ELISA, and NO generation was determined by chemiluminescence. DDAH1 overexpression exerted no effects on acute HPV. However, DDAH1 tg mice showed decreased sustained HPV compared with wild-type (WT) mice. Concomitantly, ADMA was decreased, and concentrations of NO and cGMP were significantly increased in DDAH1quinoxalin-1-one potentiated sustained HPV and partly abolished the differences in sustained HPV between WT and DDAH1 tg mice. The overexpression of DDAH1 exerted no effect on the development of chronic hypoxia-induced PH. DDAH1 overexpression selectively decreased the sustained phase of HPV, partly via activation of the NO-cGMP pathway. Thus, increased ADMA concentrations modulate sustained HPV, but not acute HPV or chronic hypoxia-induced PH.Keywords: asymmetric dimethylarginine; cyclic guanosine monophosphate; hypoxia-induced pulmonary hypertension; hypoxic pulmonary vasoconstriction; nitric oxide Exposure of the lung vasculature to hypoxia induces vasoconstriction of the precapillary vessels (hypoxic pulmonary vasoconstriction [HPV]) and, if chronic, vascular remodeling develops, fixing pulmonary hypertension (PH). HPV can be divided into two phases inducible by alveolar hypoxia, lasting seconds to minutes (acute HPV), or minutes to hours (sustained HPV). Such a biphasic response of the lung vasculature to hypoxia has been reported for isolated pulmonary arteries, as well as for isolated lungs (1, 2). Both phases of HPV play an important role in matching local perfusion to ventilation, thus optimizing pulmonary gas exchange. Acute HPV is finally triggered by an intracellular calcium increase, whereas sustained HPV additionally depends on calcium-sensitizing factors released by the endothelium, resulting in the search for an "endothelium-derived vasoconstrictive factor" (3, 4). In contrast to acute HPV, the increase of pulmonary arterial pressure (PAP) during sustained HPV is not spontaneously reversible upon reexposure to normoxia, and has been suggested to facilitate the development of PH. PH is characterized by vascular remodeling and vasoconstriction, resulting in an increased workload for the right heart. Vascular alterations in PH may also be triggered by endothelial dysfunction, resulting in smooth muscle cell proliferation, platelet aggregation, and fibroblast proliferation.Nitric oxide (NO) is one of the major endothelium-derived vasoactive mediators controlling a diverse range of pul...

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“…In addition, a role of HO-2 in the regulation of hypoxic pulmonary vasoconstriction was suggested. Against this background Roth and colleagues addressed the question of whether a complex of HO-2 and the BK channel may be important as an oxygen-sensing system underlying hypoxia-induced pulmonary hypertension and pulmonary vascular oxygen sensing (49). For this purpose investigations were performed using genetically modified mice in which HO-2 or the BK channel was deleted.…”

Section: Tyrosine Kinases and Other Pro-proliferative Pathwaysmentioning

confidence: 99%

Update on Pulmonary Hypertension 2009

Gladwin¹,

Ghofrani²

2010

Am J Respir Crit Care Med

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Heme Oxygenase-2 and Large-Conductance Ca²⁺-activated K⁺ Channels

Abstract: It is demonstrated that neither deletion of HO-2 nor BK channels affect acute, sustained, and chronic vascular responses to alveolar hypoxia in the lung.

Cited by 38 publications

References 48 publications

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Effects of Dimethylarginine Dimethylaminohydrolase–1 Overexpression on the Response of the Pulmonary Vasculature to Hypoxia

Update on Pulmonary Hypertension 2009

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Heme Oxygenase-2 and Large-Conductance Ca2+-activated K+ Channels

Abstract: It is demonstrated that neither deletion of HO-2 nor BK channels affect acute, sustained, and chronic vascular responses to alveolar hypoxia in the lung.

Cited by 38 publications

References 48 publications

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Effects of Dimethylarginine Dimethylaminohydrolase–1 Overexpression on the Response of the Pulmonary Vasculature to Hypoxia

Update on Pulmonary Hypertension 2009

Contact Info

Product

Resources

About

Heme Oxygenase-2 and Large-Conductance Ca²⁺-activated K⁺ Channels