Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 7, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp142
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Phosphorylation of connexin-43 at serine 262 promotes a cardiac injury-resistant state
Institute of Cardiovascular Sciences, St. Boniface Research Centre, and Departments of Human Anatomy and Cell Sciences, and Physiology, University of Manitoba, Winnipeg, Manitoba, Canada
Correspondence Dr. E. Kardami, Institute of Cardiovascular Sciences, St.Boniface Research Centre, 351 Taché Avenue, Winnipeg, Manitoba, Canada R2H 2A6, Tel: 204-2353519, Fax: 204-2336723, ekardami{at}sbrc.ca
AIMS: The cardioprotective agent fibroblast growth factor 2 (FGF-2) was found previously to promote phosphorylation of connexin-43 (Cx43) at protein kinase C (PKC) sites such as serine (S) 262 at levels above those of non-stimulated hearts. We asked if other PKC-dependent cardioprotective treatments cause a similar effect, and if Cx43 phosphorylation at S262 mediates resistance to injury.
METHODS: Isolated perfused adult rat hearts were subjected to the following treatments: ischemic preconditioning (PC); diazoxide perfusion; FGF-2 pre-treatment followed by 30 min global ischemia; 30 min global ischemia followed by 60 min reperfusion in the presence or absence of FGF-2. Cx43 phosphorylation was assessed by western blotting with phospho-specific antibodies. Neonatal cardiomyocyte cultures were used to examine the effect of expressing Cx43 incapable of being phosphorylated at S262 due to an S to alanine (A) substitution on simulated ischemia-induced cell death (TUNEL staining) and injury (lactic dehydrogenase release).
RESULTS: Ischemic PC, diazoxide, and FGF-2 pre-ischemic or post-ischemic treatments elicited a P*Cx43 state, defined as above-physiological levels of phospho-S262-Cx43 and phospho-S268-Cx43. P*Cx43 was sustained during global ischemia and was accompanied by attenuation of ischemia-induced Cx43 dephosphorylation and prevention of Cx43 lateralization. Post-ischemic FGF-2 treatment also diminished dephosphorylated Cx43. Modest overexpression of S262A-Cx43, but not wild-type Cx43, exacerbated cardiomyocyte death and injury caused by simulated ischemia in vitro. It also prevented the cytoprotective effects of FGF-2 or overexpressed PKC
.
CONCLUSIONS: P*Cx43 marks a state of enhanced resistance to ischemic injury promoted by PKC-activating treatments such as FGF-2 administration or ischemic PC. Cx43 phosphorylation at S262 likely mediates PKC-dependent cardioprotection.
Time for primary review: 27 Days
# Current Addresses: Department STAPS, Faculté des Sciences, Avignon, France
## Institute of Cardiovascular Disease, University of South China, Hunan, P.R. China
Wattamon Srisakuldee and Maya M Jeyaraman contributed equally to this work.
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Cardiovasc Res 2009 83: 613-614.
Cardiovasc Res 2009 83: 611-612.
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  A. Rodriguez-Sinovas Cx43 phosphorylation and cardioprotection Cardiovasc Res, September 1, 2009; 83(4): 613 - 614. [Full Text] [PDF]
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