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J Thorac Cardiovasc Surg 2009;138:1213-1221
© 2009 The American Association for Thoracic Surgery

Evolving Technology/Basic Science

Warm-blood cardioplegic arrest induces selective mitochondrial translocation of protein kinase C{epsilon} followed by interaction with 6.1 inwardly rectifying potassium channel subunit in viable myocytes overexpressing urocortin

Carol Chen-Scarabelli, MSc, FAHAa,b,*, Giuseppe Faggian, MDb, Zhaokan Yuan, PhDc, Maddalena Tessari, MScb, Alessio Rungatscher, MDb, Justin Di Rezze, BScc, Gabriele M. Scarabelli, BScc, Kadija Abounit, MScc, Roy McCauley, PhDc, Louis Saravolatz, MDc, Alessandro Mazzucco, MDb, Tiziano M. Scarabelli, MD, PhD, FAHAc

a VA Ann Arbor Healthcare System, University of Michigan, Mich
b Division of Cardiac Surgery, University of Verona, Verona, Italy
c Center for Heart and Vessel Preclinical Studies, St John Hospital and Medical Center, Wayne State University Medical School, Detroit, Mich

Received for publication June 6, 2008; revisions received February 23, 2009; accepted for publication March 28, 2009.

* Address for reprints: Carol Chen-Scarabelli, MSc, FAHA, VA Ann Arbor Healthcare System, University of Michigan, 2215 Fuller Road (111A), Ann Arbor, MI 48105. (Email: cchensc{at}med.umich.edu).

Objective: This study investigates the cardioprotective role and mechanism of action of urocortin in patients undergoing cardiac surgery, with respect to protein kinase C{epsilon} expression, activation, and relocation.

Background: Cardioplegic arrest and subsequent reperfusion inevitably expose the heart to iatrogenic ischemia/reperfusion injury. We previously reported that iatrogenic ischemia/reperfusion injury caused myocyte induction of urocortin, an endogenous cardioprotective peptide.

Methods: Two sequential biopsies were obtained from the right atrium of 25 patients undergoing coronary artery bypass grafting at the start of grafting (internal control) and 10 minutes after release of the aortic clamp.

Results: In hearts exposed to iatrogenic ischemia/reperfusion injury, induction of urocortin was documented at both the mRNA (255% of basic levels; P < .05) and the protein (4-fold increase; P < .01) levels. Iatrogenic ischemia/reperfusion injury also induced a selective increase of protein kinase C{epsilon} mRNA (225% of internal control; P < .05) and a 2-fold overexpression of total protein kinase C{epsilon} (P < .05), which paralleled a 2.9-fold increase in protein kinase C{epsilon} phosphorylation (P < .01). Mitochondrial translocation of activated protein kinase C{epsilon} was observed only in postcardioplegic samples, using both subcellular fractionation (P < .05) and immunostaining techniques (P < .05). Enhanced protein kinase C{epsilon}/mitochondria colocalization was selectively observed in viable myocytes, showing concurrently positive staining for urocortin (P < .05). Finally, co immunoprecipitation experiments documented an iatrogenic ischemia/reperfusion injury-enhanced physical interaction of phosphorylated protein kinase C{epsilon} with the 6.1 inwardly rectifying potassium channel subunit of the KATP channels (P < .05).

Conclusion: After iatrogenic ischemia/reperfusion injury, urocortin expression in viable cells selectively colocalized with enhanced phosphorylation and mitochondrial relocation of protein kinase C{epsilon}, suggesting a cardioprotective role for endogenous urocortin. The physical interaction of activated protein kinase C{epsilon} with 6.1 inwardly rectifying potassium channel, enhanced by cardioplegic arrest, may represent a conjectural mechanism of urocortin-mediated cardioprotection.

Abbreviations and Acronyms ATP = adenosine-5'-triphosphate; CABG = coronary artery bypass graft; Hsp = heat shock protein; iIRI = iatrogenic ischemia/reperfusion injury; I/R = ischemia/reperfusion; Kir6.1 = 6.1 inwardly rectifying potassium channel; Kir6.2 = 6.2 inwardly rectifying potassium channel; PCR = polymerase chain reaction; PKC = protein kinase C; SDS-PAGE = sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SUR = sulfonylurea receptor; TUNEL = terminal deoxynucleotidyl transferase-mediated nick end labeling; Ucn = urocortin






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