Targeted disruption of the protein kinase C epsilon gene abolishes the infarct size reduction that follows ischaemic preconditioning of isolated buffer-perfused mouse hearts.
OBJECTIVE
Activation of protein kinase C (PKC) isoforms is associated with the cardioprotective effect of early ischaemic preconditioning (IP). PKC consists of at least 10 different isoforms, encoded by separate genes, which mediate distinct physiological functions. Although the PKC-epsilon isoform has been implicated in preconditioning, uncertainty remains. We investigated whether preconditioning still occurs in a mouse line lacking cardiac PKC-epsilon protein due to a targeted disruption within the pkc-epsilon allele.


METHODS
The isolated buffer-perfused hearts from knockout mice lacking PKC-epsilon (-/-) and sibling heterozygous mice (+/-), with a normal PKC-epsilon complement, were preconditioned by 4 x 4 min ischaemia/6 min reperfusion. Hearts then underwent 45 min of global ischaemia followed by 1.5 h of reperfusion.


RESULTS
In PKC-epsilon (+/-) hearts ischaemic preconditioning reduced infarction volume as a percentage of myocardial volume (24.3+/-4.5 vs. 41.3+/-4.7%, P<0.001). In contrast, in PKC-epsilon (-/-) hearts preconditioning failed to diminish infarction (36.4+/-2.9 vs. 38.8+/-4.5%). Surprisingly however, although preconditioning did not reduce infarct size, it did enhance contractile recovery in PKC-epsilon (-/-) mice (43.1+/-3.9 vs. 24.9+/-5.1%, P<0.05), similar to the level seen in PKC-epsilon (+/-) hearts (35.2+/-3.9 vs. 20.9+/-5.0%, P<0.05).


CONCLUSIONS
These data suggest that PKC-epsilon is essential for the reduction in infarction that follows early ischaemic preconditioning, but is not associated with the improvement in functional recovery.
Saurin
Adrian T
AT
Department of Cardiology, KCL, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, UK. adrian.saurin@kcl.ac.uk
Pennington
Daniel J
DJ
Raat
Nicolaas J H
NJ
Latchman
David S
DS
Owen
Michael J
MJ
Marber
Michael S
MS
D000704:Analysis of Variance; D000818:Animals; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D010477:Perfusion; D011493:Protein Kinase C / Q000235:genetics*
D007527:Isoenzymes; D011493:Protein Kinase C