title: The natural cardioprotective particle HDL modulates connexin43 gap junction channels.
abstract: OBJECTIVE
  High-density lipoprotein (HDL) is known for its cardioprotective properties independent from its cholesterol transport activity. These properties are mediated by activation of kinases such as protein kinase C (PKC). Connexin43 (Cx43) is a gap junction protein present in ventricular cardiomyocytes. PKC-dependent phosphorylation modifies Cx43 gap junction channel properties and is involved in cardioprotection. We hypothesized that cardioprotective properties of HDL may be mediated in part by affecting Cx43 gap junction channels.
  
  
  RESULTS
  Neonatal rat cardiomyocytes were treated with HDL and Cx43 phosphorylation was evaluated by western blotting and immunofluorescence. We found that HDL promoted phosphorylation of Cx43 with a maximal induction at 5 min, which was inhibited by pre-treatment with various PKC inhibitors. Sphingosine-1-phosphate (S1P), a component of HDL, induced effects that were similar to those of HDL. These compounds significantly reduced diffusion of fluorescent dye among cardiomyocytes (∼50%) which could be prevented by PKC inhibition. As observed during optical recordings of transmembrane voltage, HDL and S1P depressed impulse conduction only minimally (<5%). Moreover, 5 min of HDL and S1P treatment at the onset of reperfusion significantly reduced infarct size (∼50%) in response to 30 min ischaemia in ex vivo experiments.
  
  
  CONCLUSIONS
  Short-term treatment with HDL or S1P induces phosphorylation of Cx43 by a PKC-dependent pathway. HDL-induced phosphorylation of Cx43 reduced the diffusion of large tracer molecules between cells, whereas impulse conduction was maintained. Moreover, 5 min treatment with HDL confers cardioprotection against ischaemia/reperfusion injury. These results link Cx43 for the first time to the short-term cardioprotective effects of HDL.
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Foundation for Medical Research, Switzerland. sandrine.morel@unige.ch
authors.forename: Sandrine
authors.initials: S
authors.lastname: Morel
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Frias
authors.forename: Christian
authors.initials: C
authors.lastname: Rosker
authors.forename: Richard W
authors.initials: RW
authors.lastname: James
authors.forename: Stephan
authors.initials: S
authors.lastname: Rohr
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Kwak
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology*; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D018031:Connexin 43; C543076:GJA1 protein, mouse; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D011493:Protein Kinase C; D013110:Sphingosine