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Ann Thorac Surg 2002;73:1236-1245
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Protective effects of protein kinase C during myocardial ischemia require activation of phosphatidyl-inositol specific phospholipase C

Mamoru Munakata, MDa, Christof Stamm, MDa, Ingeborg Friehs, MDa, David Zurakowski, PhDb, Douglas B. Cowan, PhDc, Hung Cao-Danh, PhDa, Francis X. McGowan, Jr, MDc, Pedro J. del Nido, MD*a

a Department of Pediatric Cardiac Surgery, Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
b Department of Biostatistics, Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
c Department of Pediatric Anesthesiology/Critical Care, Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

Accepted for publication November 28, 2001.

* Address reprint requests to Dr del Nido, Department of Cardiac Surgery, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115 USA
e-mail: pedro.delnido{at}tch.harvard.edu

Background. Protein kinase C (PKC) activation during myocardial ischemia is thought to be cardioprotective. However, the mechanism of ischemia-induced PKC activation remains unclear. We hypothesized that ischemic PKC activation occurs through activation of phosphatidyl-inositol specific phospholipase C (PI-PLC) and protects the heart from ischemic injury.

Methods. Isolated rabbit hearts were subjected to 20 minutes of normothermic ischemia and reperfusion. The PI-PLC inhibitor U73122 (0.5 µmol/L), its inactive analogue U73343 (0.5 µmol/L), or the PKC inhibitor chelerythrine (2 µmol/L) were given just before ischemia. Another group received U73122 plus the direct PKC activator phorbol 12-myristate-13-acetate (PMA, 10 pmol/L). Measurements included contractile function, intracellular calcium, PI-PLC activity, and translocation of PKC isoforms.

Results. PI-PLC activity increased during myocardial ischemia and was inhibited by U73122. PI-PLC inhibition prevented the ischemic translocation of PKC-{alpha}, PKC-{varepsilon}, and PKC-{eta}, and impaired cardiac recovery and cytosolic calcium regulation without significant changes in energy metabolism. PMA restored both contractile function and PKC translocation pattern in U73122-treated hearts. Direct PKC inhibition with chelerythrine mimicked the effects of U73122.

Conclusions. PI-PLC mediates PKC translocation during myocardial ischemia. Inhibition of PI-PLC or PKC activation, or both, during ischemia significantly impairs postischemic myocardial recovery.


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Invited commentary
Hikaru Matsuda
Ann. Thorac. Surg. 2002 73: 1245. [Extract] [Full Text] [PDF]



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