Retraction notice to Docosahexaenoic acid attenuates hypoxic pulmonary vasoconstriction by activating the large conductance Ca2+-activated K+ currents in pulmonary artery smooth muscle cells [Pulm. Pharmacol. Therap., 28/1 (2013) 9–16]

Hypoxic pulmonary vasoconstriction is caused by a rise in cytosolic Ca2+ ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) via multiple mechanisms. PASMC consist of heterogeneous phenotypes defined by contractility, proliferation, and apoptosis as well as by differences in expression and function of various genes. In rat PASMC, hypoxia-mediated decrease in voltage-gated K+ (Kv) currents ( IK(V)) and increase in [Ca2+]cyt were not uniformly distributed in all PASMC tested. Acute hypoxia decreased IK(V) and increased [Ca2+]cyt in ∼46% and ∼53% of PASMC, respectively. Using combined techniques of single-cell RT-PCR and patch clamp, we show here that mRNA expression level of Kv1.5 in hypoxia-sensitive PASMC (in which hypoxia reduced IK(V)) was much greater than in hypoxia-insensitive cells (in which hypoxia negligibly affected IK(V)). These results demonstrate that 1) different PASMC express different Kv channel α- and β-subunits, and 2) the sensitivity of a PASMC to acute hypoxia partially depends on the expression level of Kv1.5 channels; hypoxia reduces whole-cell IK(V) only in PASMC that express high level of Kv1.5. In addition, the acute hypoxia-mediated changes in [Ca2+]cyt also vary in different PASMC. Hypoxia increases [Ca2+]cyt only in 34% of cells tested, and the different sensitivity of [Ca2+]cyt to hypoxia was not related to the resting [Ca2+]cyt. An intrinsic mechanism within each individual cell may be involved in the heterogeneity of hypoxia-mediated effect on [Ca2+]cyt in PASMC. These data suggest that the heterogeneity of PASMC may partially be related to different expression levels and functional sensitivity of Kv channels to hypoxia and to differences in intrinsic mechanisms involved in regulating [Ca2+]cyt.

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Docosahexaenoic acid inhibits Ca 2+ influx and downregulates CaSR by upregulating microRNA‐16 in pulmonary artery smooth muscle cells

Journal of Biochemical and Molecular Toxicology ◽

10.1002/jbt.22573 ◽

2020 ◽

Vol 34 (11) ◽

Author(s):

Jin‐jun Liu ◽

Ming‐ming Tang ◽

Ming‐li Zhu ◽

Cai‐xia Xie ◽

Pin‐fang Kang ◽

...

Keyword(s):

Smooth Muscle ◽

Docosahexaenoic Acid ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Pulmonary Artery Smooth Muscle

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Diphenyleneiodonium inhibits both potassium and calcium currents in isolated pulmonary artery smooth muscle cells

Journal of Applied Physiology ◽

10.1152/jappl.1994.76.6.2611 ◽

1994 ◽

Vol 76 (6) ◽

pp. 2611-2615 ◽

Cited By ~ 61

Author(s):

E. K. Weir ◽

C. N. Wyatt ◽

H. L. Reeve ◽

J. Huang ◽

S. L. Archer ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Smooth Muscle ◽

Nadph Oxidase ◽

Smooth Muscle Cells ◽

Hypoxic Pulmonary Vasoconstriction ◽

Muscle Cells ◽

Calcium Currents ◽

Pulmonary Vasoconstriction ◽

Pulmonary Artery Smooth Muscle ◽

Isolated Pulmonary Artery

Diphenyleneiodonium (DPI) blocks hypoxic vasoconstriction in the pulmonary vasculature. Because one of the actions of DPI is the inhibition of NADPH oxidase, this has led to the suggestion that NADPH oxidase acts as an oxygen tension sensor in pulmonary smooth muscle cells. We investigated the effects of DPI on potassium and calcium currents in freshly isolated pulmonary artery smooth muscle cells by using whole cell patch-clamp recordings, since these ionic currents are known to be involved in hypoxic pulmonary vasoconstriction. DPI (3 and 10 microM) reversibly inhibited potassium currents, and in its presence, residual currents appeared markedly more transient than under control conditions. The actions of DPI could not be reversed by 4.4 mM hydrogen peroxide, the product of NADPH oxidase. Calcium channel currents were also reversibly inhibited by 3 microM DPI. Thus DPI is a nonselective blocker of ionic channels in pulmonary smooth muscle cells, and its mechanism of action does not appear to involve inhibition of hydrogen peroxide formation. The ability of DPI to block calcium currents can explain its inhibition of hypoxic pulmonary vasoconstriction.

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A role for receptor-operated Ca2+ entry in human pulmonary artery smooth muscle cells in response to hypoxia

Physiological Research ◽

10.33549/physiolres.931875 ◽

2010 ◽

pp. 909-918 ◽

Cited By ~ 1

Author(s):

C Tang ◽

WK To ◽

F Meng ◽

Y Wang ◽

Y Gu

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Hypoxic Pulmonary Vasoconstriction ◽

Muscle Cells ◽

Trpc Channels ◽

Hypoxia Response ◽

Compound C ◽

Pulmonary Artery Smooth Muscle ◽

Human Pulmonary Artery

Hypoxic pulmonary vasoconstriction (HPV) is an important homeostatic mechanism in which increases of [Ca2+]i are primary events. In this study, primary cultured, human pulmonary artery smooth muscle cells (hPASMC) were used to examine the role of TRPC channels in mediating [Ca2+]i elevations during hypoxia. Hypoxia (PO2 about 20 mm Hg) evoked a transient [Ca2+]i elevation that was reduced by removal of extracellular calcium. Nifedipine and verapamil, blockers of voltage-gated calcium channels (VGCCs), attenuated the hypoxia-induced [Ca2+]i elevation by about 30 %, suggesting the presence of alternate Ca2+ entry pathways. Expression of TRPC1 and TRPC6 in hPASMC were found by RT-PCR and confirmed by Western blot analysis. Antagonists for TRPC, 2APB and SKF96365, significantly reduced hypoxia-induced [Ca2+]i elevation by almost 60 %. Both TRPC6 and TRPC1 were knocked down by siRNA, the loss of TRPC6 decreased hypoxic response down to 21 % of control, whereas the knockdown of TRPC1 reduced the hypoxia response to 85 %, suggesting that TRPC6 might play a central role in mediating hypoxia response in hPASMC. However, blockade of PLC pathway caused only small inhibition of the hypoxia response. In contrast, AICAR, the agonist of AMP-activated kinase (AMPK), induced a gradual [Ca2+]i elevation, whereas compound C, an antagonist of AMPK, almost abolished the hypoxia response. However, co-immunoprecipitation revealed that AMPKα was not colocalized with TRPC6. Our data supports a role for TRPC6 in mediation of the [Ca2+]i elevation in response to hypoxia in hPASMC and suggests that this response may be linked to cellular energy status via an activation of AMPK.

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Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction

AJP Cell Physiology ◽

10.1152/ajpcell.1992.262.4.c882 ◽

1992 ◽

Vol 262 (4) ◽

pp. C882-C890 ◽

Cited By ~ 324

Author(s):

J. M. Post ◽

J. R. Hume ◽

S. L. Archer ◽

E. K. Weir

Keyword(s):

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Hypoxic Pulmonary Vasoconstriction ◽

K Channel ◽

Pulmonary Vasoconstriction ◽

Channel Inhibition ◽

Pulmonary Arterial ◽

Arterial Smooth Muscle Cells ◽

K Currents

Cellular mechanisms responsible for hypoxic pulmonary vasoconstriction were investigated in pulmonary arterial cells, isolated perfused lung, and pulmonary artery rings. Three K+ channel antagonists, Leiurus quinquestriatus venom, tetraethylammonium, and 4-aminopyridine, mimicked the effects of hypoxia in isolated lung and arterial rings by increasing pulmonary artery pressure and tension and also inhibited whole cell K+ currents in isolated pulmonary arterial cells. Reduction of oxygen tension from normoxic to hypoxic levels directly inhibited K+ currents and caused membrane depolarization in isolated canine pulmonary arterial smooth muscle cells but not in canine renal arterial smooth muscle cells. Nisoldipine or high buffering of intracellular Ca2+ concentration with [1,2-bis(2)aminophenoxy] ethane-N,N,N',N'-tetraacetic acid prevented hypoxic inhibition of K+ current, suggesting that a Ca(2+)-sensitive K+ channel may be responsible for the hypoxic response. These results indicate that K+ channel inhibition may be a key event that links hypoxia to pulmonary vasoconstriction by causing membrane depolarization and subsequent Ca2+ entry.

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