Cardiovascular Research Advance Access originally published online on May 7, 2009
Cardiovascular Research 2009 83(4):672-681; doi:10.1093/cvr/cvp142
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Phosphorylation of connexin-43 at serine 262 promotes a cardiac injury-resistant state
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1 Institute of Cardiovascular Sciences, St Boniface Research Centre, 351 Taché Avenue, Winnipeg, Manitoba, Canada R2H 2A6
2 Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada
3 Department of Human Anatomy and Cell Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
* Corresponding author. Tel: +1 204 2353519; fax: +1 204 2336723. E-mail address: 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 and results: Isolated perfused adult rat hearts were subjected to the following treatments: ischaemic preconditioning (PC); diazoxide perfusion; FGF-2 pre-treatment followed by 30 min global ischaemia; 30 min global ischaemia 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 ischaemia-induced cell death (TUNEL staining) and injury (lactic dehydrogenase release). Ischaemic PC, diazoxide, and FGF-2 pre-ischaemic or post-ischaemic treatments elicited a P*Cx43 state, defined as above-physiological levels of phospho-S262-Cx43 and phospho-S368-Cx43. P*Cx43 was sustained during global ischaemia and was accompanied by attenuation of ischaemia-induced Cx43 dephosphorylation and prevention of Cx43 lateralization. Post-ischaemic 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 ischaemia in vitro. It also prevented the cytoprotective effects of FGF-2 or overexpressed PKC
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Conclusions: P*Cx43 marks a state of enhanced resistance to ischaemic injury promoted by PKC-activating treatments such as FGF-2 administration or ischaemic PC. Cx43 phosphorylation at S262 likely mediates PKC-dependent cardioprotection.
KEYWORDS Fibroblast growth factor-2; Preconditioning; Post-conditioning; Connexin43; Phosphorylation; Protein kinase C
Time for primary review: 27 days
Present address. Department STAPS, Faculté des Sciences, Avignon, France.
Present address. Institute of Cardiovascular Disease, University of South China, Hunan, People's Republic of China.
These authors 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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