Pulmonary artery smooth muscle cell [Ca2+]i and contraction: responses to diphenyleneiodonium and hypoxia

Zhang, F.; Carson, Roger C.; Zhang, H.; Gibson, Gary E.; Thomas, Hugh

doi:10.1152/ajplung.1997.273.3.l603

Cited by 32 publications

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“…dcEF stimulation also more than doubles [Ca 2+ ]i in a rat osteoblast-like cell line (Wang et al, 1998). Moreover, note that Ca 2+ influx induced by various factors, including membrane depolarization, has a role in cellular contraction (see below) in hepatic stellate cells (Bataller et al, 2001), pulmonary artery smooth muscle (Zhang et al, 1997) and skeletal muscle cells (Mickleson and Louis, 1996). The commonly seen cathodal galvanotaxis of cells can be explained if one assumes that, as a consequence of the dcEF, a rise in [Ca 2+ ]i in a given part of the cell causes contraction of that side whereas the opposite occurs at the other side.…”

Section: The Importance Of Ca 2+mentioning

confidence: 95%

Cellular mechanisms of direct-current electric field effects: galvanotaxis and metastatic disease

Mycielska

Djamgoz

2004

Journal of Cell Science

327

300

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Endogenous direct-current electric fields (dcEFs) occur in vivo in the form of epithelial transcellular potentials or neuronal field potentials, and a variety of cells respond to dcEFs in vitro by directional movement. This is termed galvanotaxis. The passive influx of Ca2+ on the anodal side should increase the local intracellular Ca2+ concentration, whereas passive efflux and/or intracellular redistribution decrease the local intracellular Ca2+ concentration on the cathodal side. These changes could give rise to `push-pull' effects, causing net movement of cells towards the cathode. However, such effects would be complicated in cells that possess voltage-gated Ca2+ channels and/or intracellular Ca2+ stores. Moreover, voltage-gated Na+ channels, protein kinases, growth factors, surface charge and electrophoresis of proteins have been found to be involved in galvanotaxis. Galvanotactic mechanisms might operate in both the short term (seconds to minutes) and the long term (minutes to hours), and recent work has shown that they might be involved in metastatic disease. The galvanotactic responses of strongly metastatic prostate and breast cancer cells are much more prominent, and the cells move in the opposite direction compared with corresponding weakly metastatic cells. This could have important implications for the metastatic process and has clinical implications. Galvanotaxis could thus play a significant role in both cellular physiology and pathophysiology.

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Section: The Importance Of Ca 2+mentioning

confidence: 95%

Cellular mechanisms of direct-current electric field effects: galvanotaxis and metastatic disease

Mycielska

Djamgoz

2004

Journal of Cell Science

327

300

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“…vascular smooth muscle; endothelium; nitric oxide; Rho kinase; temperature; endothelin-1; N -nitro-L-arginine methyl ester; Y-27632 HYPOXIC PULMONARY VASOCONSTRICTION (HPV) is thought to result from an increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) in pulmonary arterial smooth muscle cells (PASMC) (37,40,48,51,52,54,56,62,72,77,82). The increased [Ca 2ϩ ] i leads in turn to calmodulin-dependent activation of myosin light chain (MLC) kinase (MLCK), MLCK-dependent phosphorylation of the 20-kDa regulatory MLC (P-MLC 20 ), P-MLC 20 -dependent activation of the actin-myosin interaction, and PASMC contraction (38,42,74,75,83).…”

mentioning

confidence: 99%

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

Weigand

Shimoda

Sylvester

2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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(37,40,48,51,52,54,56,62,72,77,82). The increased [Ca 2ϩ ] i leads in turn to calmodulin-dependent activation of myosin light chain (MLC) kinase (MLCK), MLCK-dependent phosphorylation of the 20-kDa regulatory MLC (P-MLC 20 ), P-MLC 20 -dependent activation of the actin-myosin interaction, and PASMC contraction (38,42,74,75,83 ] i during the slowly developing phase 2 contraction (52). Endothelial denudation did not alter the [Ca 2ϩ ] i response to hypoxia but abolished phase 2 contraction (51). These results suggest that phase 2 contraction resulted from an increase in PASMC Ca 2ϩ sensitivity and that this sensitization was due to release of factors from endothelial cells, rather than direct effects of hypoxia on smooth muscle. The identities of these factors remain unknown; however, antagonists of endothelin-1 (ET-1) had no effect on phase 2 HPV in endothelium-intact IPA, suggesting that ET-1 played no role (51). Although the nitric oxide/guanylate cyclase/protein kinase G (NO/GC/PKG) transduction pathway can alter Ca 2ϩ sensitivity in pulmonary arteries (27, 57), its effect on Ca 2ϩ sensitivity during acute hypoxia has not been examined.Consistent with endothelium dependence, hypoxia did not change steady-state isometric force achieved during normoxia at [Ca 2ϩ ] i ϭ 3-1,000 nM in endothelium-denuded rat extrapulmonary arteries permeabilized with ␤-escin and exposed to phorbol-12,13-dibutyrate, a protein kinase C activator, at 30°C (58); however, an effect of hypoxia may have been precluded in these experiments by use of proximal pulmonary arteries, which have weak contractile responses to hypoxia (39,40,61,65); phorbol-12,13-dibutyrate, which enhances Ca 2ϩ sensitivity on its own (30, 59); and low temperature, which inhibits HPV (4,21,36). Hypoxia also did not alter the relation between increases in [Ca 2ϩ ] i and decreases in cell length induced by the Ca 2ϩ ionophore 4-bromo-A-23187 in freshly isolated porcine distal PASMC at 37°C (62); however, since these cells were variably attached to glass coverslips, uneven loading among cells and the absence of isotonic conditions may have obscured possible effects of hypoxia.Many stimuli increase myofilament Ca 2ϩ sensitivity by decreasing activity of MLC phosphatase (MLCP), the enzyme responsible for dephosphorylation and inactivation of P-MLC 20 . Decreased MLCP activity leads to [Ca 2ϩ ] i -independent increases in P-MLC 20 concentration ([P-MLC 20 ]), actin-myosin interaction, and contraction (66), and can be achieved by upregulation of signals causing MLCP inhibition, such as those generated by Rho kinase (31, 66), or downregulation of signals causing MLCP activation, such as those generated by NO/GC/PKG (35,66). Among these possibilities, Rho kinase has been the most studied in PASMC during hypoxia.

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“…[1][2][3][4][5][6] Rings of pulmonary artery (PA) constrict under low O 2 conditions 7,8 even if denuded of endothelium. 9,10 Even isolated PA myocytes contract during hypoxia, 11 indicating that the O 2 sensor is intrinsic to those cells.…”

mentioning

confidence: 99%

Model for Hypoxic Pulmonary Vasoconstriction Involving Mitochondrial Oxygen Sensing

Waypa

Chandel

Schumacker

2001

Circulation Research

344

348

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Abstract-We tested whether mitochondria function as the O 2 sensor underlying hypoxic pulmonary vasoconstriction (HPV). In buffer-perfused rat lungs, rotenone, myxothiazol, and diphenyleneiodonium, which inhibit mitochondria in the proximal region of the electron transport chain (ETC), abolished HPV without attenuating the response to U46619. Cyanide and antimycin A inhibit electron transfer in the distal region of the ETC, but they did not abolish HPV. Cultured pulmonary artery (PA) myocytes contract in response to hypoxia or to U46619. The hypoxic response was abolished while the response to U46619 was maintained in mutant ( 0 ) PA myocytes lacking a mitochondrial ETC. To test whether reactive oxygen species (ROS) derived from mitochondria act as signaling agents in HPV, the antioxidants pyrrolidinedithiocarbamate and ebselen and the Cu,Zn superoxide dismutase inhibitor diethyldithiocarbamate were used. These abolished HPV without affecting contraction to U46619, suggesting that ROS act as second messengers. In cultured PA myocytes, oxidation of intracellular 2Ј,7Ј-dichlorofluorescin diacetate (DCFH) dye increased under 2% O 2 , indicating that myocytes increase their generation of H 2 O 2 during hypoxia. This was attenuated by myxothiazol, implicating mitochondria as the source of increased ROS during HPV. These results indicate that mitochondrial ATP is not required for HPV, that mitochondria function as O 2 sensors during hypoxia, and that ROS generated in the proximal region of the ETC act as second messengers in the response. Key Words: reactive oxygen species Ⅲ hypoxia Ⅲ redox signaling Ⅲ pulmonary circulation Ⅲ oxidants H ypoxic pulmonary vasoconstriction (HPV) diverts blood flow away from the lung during fetal development and optimizes lung gas exchange after birth by enhancing the matching of blood flow and ventilation. Excised lungs retain the HPV response. 1-6 Rings of pulmonary artery (PA) constrict under low O 2 conditions 7,8 even if denuded of endothelium. 9,10 Even isolated PA myocytes contract during hypoxia, 11 indicating that the O 2 sensor is intrinsic to those cells.Although HPV has been well characterized, the underlying mechanism of O 2 sensing is not established. Among the putative O 2 sensors that have been proposed, mitochondria have been discounted because the K m of cytochrome oxidase for O 2 is too low to permit detection of physiological hypoxia. 12 Moreover, inhibition of cytochrome oxidase with cyanide failed to abolish HPV. 2 However, our studies have implicated mitochondria in the O 2 sensing underlying functional and transcriptional responses to hypoxia in other cells. [13][14][15] Those data suggest that mitochondria generate reactive oxygen species (ROS) in response to low PO 2 , which constitutes an O 2 -dependent signal. 14,15 Oxidant signaling during hypoxia appears to originate at complex III, which could continue to function despite inhibition of complex IV with cyanide. The present study sought to determine whether mitochondria also function as the O 2 sensor during H...

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Pulmonary artery smooth muscle cell [Ca2+]i and contraction: responses to diphenyleneiodonium and hypoxia

Cited by 32 publications

References 0 publications

Cellular mechanisms of direct-current electric field effects: galvanotaxis and metastatic disease

Cellular mechanisms of direct-current electric field effects: galvanotaxis and metastatic disease

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

Model for Hypoxic Pulmonary Vasoconstriction Involving Mitochondrial Oxygen Sensing

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