Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 5, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn148
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Identification and Physiological Activity of Survival Factor Released from Cardiomyocytes during Ischemia and Reperfusion
1 From the Center for Gene Research, Yamaguchi University, Yamaguchi, 755-8505
2 Department of Physiology, Akita University School of Medicine, Akita, 010-8543
3 Department of Clinical Pharmacology, Kyushu University Graduate School of Medicine, Fukuoka, 812-8582
4 Department of Cell Physiology Faculty of Medicine, Kagawa University, Kagawa, 761-0793
5 Department of Molecular Cardiovascular Biology Yamaguchi University School of Medicine, Yamaguchi, 755-8505
6 Department of Surgery and Clinical Science, Yamaguchi University School of Medicine, Yamaguchi, 755-8505
Correspondence to: Yoichi Mizukami The Center for Gene Research, Yamaguchi University School of Medicine 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan Tel: +81-836-22-2183 Fax: +81-836-22-2185 E-mail: mizukami{at}yamaguchi-u.ac.jp
Aims: We carried out a screening of survival factors released from cells exposed to simulated ischemia and reperfusion (sI/R) using the embryonic rat heart-derived cell line H9c2 and examined the physiological role of the identified factor.
Method: The culture medium supernatant of H9c2 cells exposed to sI/R was separated by column chromatography, and the fractions examined for survival activity. The protein with survival activity was identified by mass spectrometry, and its physiological role was examined in models of ischemia.
Results: Cell survival activity was detected in at least three fractions of the cell supernatant collected during sI/R and subjected to a series of column chromatographic steps. Among the proteins measured by mass spectrometry and western blotting, a p36 protein identified as a glycolytic enzyme, lactate dehydrogenase muscle subunit (M-LDH), showed strong survival activity. H2O2-induced intracellular calcium overload in H9c2 cells and irregular Ca2+ transients in adult rat cardiomyocytes were both found to be inhibited by pretreatment with M-LDH. M-LDH also lowered the frequency and amplitude of early afterdepolarizations induced by H2O2 in adult rat cardiomyocytes and suppressed the ischemia/reperfusion -induced reduction of cardiac output from mouse working heart preparations. M-LDH was found to increase the phosphorylation of extracellular signal-regulated kinase1/2, which plays a role in H9c2 cell survival.
Conclusion: M-LDH released from cardiomyocytes after hypoxia and reoxygenation has a role in protecting the heart from oxidative stress-induced injury through an intracellular signal transduction pathway involving extracellular signal-regulated kinase1/2.
KEYWORDS M-LDH; survival factor; cardiomyocyte; secretion; ischemia
Time for primary review: 25 days
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Cardiovasc Res 2008 79: 545-546.
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  A. Lochner Sarcolemmal permeability changes during ischaemia and reperfusion: release of survival factors Cardiovasc Res, September 1, 2008; 79(4): 545 - 546. [Full Text] [PDF]
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