Hypoxia in high glucose followed by reoxygenation in normal glucose reduces the viability of cortical astrocytes through increased permeability of connexin 43 hemichannels.
Brain ischemia causes more extensive injury in hyperglycemic than normoglycemic subjects, and the increased damage is to astroglia as well as neurons. In the present work, we found that in cortical astrocytes from rat or mouse, reoxygenation after hypoxia in a medium mimicking interstitial fluid during ischemia increases hemichannel activity and decreases cell-cell communication via gap junctions as indicated by dye uptake and dye coupling, respectively. These effects were potentiated by high glucose during the hypoxia in a concentration-dependent manner (and by zero glucose) and were not observed in connexin 43(-/-) astrocytes. The responses were transient and persistent after short and long periods of hypoxia, respectively. The persistent responses were associated with a progressive reduction in cell viability that was prevented by La(3+) or peptides that block connexin 43 (Cx43) hemichannels or by inhibition of p38 MAP kinase prior to hypoxia-reoxygenation but not by treatments that block pannexin hemichannels. Block of Cx43 hemichannels did not affect the reduction in gap junction mediated dye coupling observed during reoxygenation. Cx43 hemichannels may be a novel therapeutic target to reduce cell death following stroke, particularly in hyperglycemic conditions.
Orellana
Juan A
JA
Departamento de Ciencias Fisiológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile. jaorella@uc.cl
Hernández
Diego E
DE
Ezan
Pascal
P
Velarde
Victoria
V
Bennett
Michael V L
MV
Giaume
Christian
C
Sáez
Juan C
JC
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000503:physiopathology; D018031:Connexin 43 / Q000187:drug effects / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000503:physiopathology; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000503:physiopathology; D007811:Lanthanum / Q000494:pharmacology; D051379:Mice; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology
D018031:Connexin 43; D005456:Fluorescent Dyes; D010455:Peptides; D007811:Lanthanum; D005947:Glucose; D010100:Oxygen
J Neurosci Res. 2009 May 1;87(6):1375-80
19084903
Physiol Rev. 2003 Oct;83(4):1359-400
14506308
Neuropathol Appl Neurobiol. 2003 Aug;29(4):350-60
12887595
J Neurosci. 2007 Dec 12;27(50):13781-92
18077690
Biol Chem. 2005 Apr;386(4):325-32
15899694
Cell Commun Adhes. 2007 Nov-Dec;14(6):265-73
18392994
Mol Biol Cell. 2007 Feb;18(2):337-47
17108328
J Cereb Blood Flow Metab. 2003 Jan;23(1):23-33
12500088
Proc Natl Acad Sci U S A. 2007 May 15;104(20):8322-7
17494739
Trends Neurosci. 1999 Sep;22(9):391-7
10441299
Neuroscience. 1996 Apr;71(3):855-70
8867054
Brain Res Brain Res Rev. 2000 Apr;32(1):250-8
10751675
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11388-93
13130072
Antioxid Redox Signal. 2009 Feb;11(2):369-99
18816186
Diabetes. 2006 Feb;55(2):349-55
16443767
Glia. 2005 Jun;50(4):427-34
15846805
Cell Commun Adhes. 2001;8(4-6):383-6
12064623
Nat Rev Neurosci. 2006 Jun;7(6):437-48
16715053
J Mol Cell Cardiol. 2000 Oct;32(10):1859-72
11013130
J Neurosci. 1987 Feb;7(2):357-68
2880937
Science. 2002 Apr 19;296(5567):503-7
11964472
J Neurotrauma. 2002 Jan;19(1):85-98
11852981
Am J Physiol Cell Physiol. 2008 Sep;295(3):C761-7
18596212
Brain Res. 1997 Apr 25;755(1):36-46
9163539
Science. 2002 Oct 18;298(5593):556-62
12386325
Arch Neurol. 2001 Aug;58(8):1209-12
11493160
Cell Death Differ. 2007 Jul;14(7):1324-35
17431421
Brain Res Brain Res Rev. 1999 Apr;29(2-3):137-68
10209230
Glia. 2007 Jan 1;55(1):46-56
17009242
Am J Physiol Cell Physiol. 2007 Sep;293(3):C1112-9
17652431
Neuroscience. 1997 May;78(2):589-601
9145812
Mol Biol Cell. 2008 Aug;19(8):3501-13
18495870
Mol Biol Cell. 2005 Nov;16(11):5247-57
16135529
Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4475-80
16537412
EMBO J. 2006 Nov 1;25(21):5071-82
17036048
Cancer Chemother Pharmacol. 2008 Apr;61(4):639-45
17609948
Arch Neurol. 1977 Feb;34(2):65-74
402127
Biochim Biophys Acta. 2005 Jun 10;1711(2):215-24
15955306
J Neurosci. 1993 Aug;13(8):3510-24
8101871
Anticancer Res. 2006 Nov-Dec;26(6B):4155-62
17201127
Stroke. 2004 Mar;35(3):753-7
14963271
J Biol Chem. 1996 Feb 23;271(8):4138-42
8626753
Glia. 2001 Apr 15;34(2):134-42
11307162
J Neurochem. 2006 Nov;99(4):1049-61
16899068
Stroke. 1995 Sep;26(9):1634-8
7660410
Neuroscience. 2004;129(4):877-96
15561405