© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Post-ischemic PKC inhibition impairs myocardial calcium handling and increases contractile protein calcium sensitivity
aDepartment of Cardiac Surgery, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
bDepartment of Anesthesia, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
cDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada M5G 2C4
* Corresponding author. Tel.: +1-617-355-8290; fax: +1-617-232-2697 delnido{at}cardio.tch.harvard.edu
Objective: Protein kinase C (PKC) activation impairs contractility in the normal heart but is protective during myocardial ischemia. We hypothesized that PKC remains activated post-ischemia and modulates myocardial excitation–contraction coupling during early reperfusion. Methods: Langendorff-perfused rabbit hearts where subjected to 25 min unmodified ischemia and 30 min reperfusion. Total PKC activity was measured, and the intracellular translocation pattern of PKC-
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assessed by immunohistochemistry and fractionated Western immunoblotting. The PKC-inhibitors chelerythrine and GF109203X were added during reperfusion and also given to non-ischemic hearts. Measurements included left ventricular function, intracellular calcium handling measured by Rhod-2 spectrofluorometry, myofibrillar calcium responsiveness in beating and tetanized hearts, and metabolic parameters. Results: Total PKC activity was increased at end-ischemia and remained elevated after 30 min of reperfusion. The translocation pattern indicated PKC-
as the main active isoform during reperfusion. Post-ischemic PKC inhibition affected mainly diastolic relaxation, with lesser effect on contractility. Both PKC inhibitors increased the Ca2+ responsiveness of the myofilaments as indicated by a leftward shift of the calcium-to-force relationship and increased maximum calcium activated tetanic pressure. Diastolic Ca2+ removal was delayed and the post-ischemic [Ca2+]i overload further exacerbated. Depressed systolic function was associated with a lower amplitude of [Ca2+]i transients. Conclusion: PKC is activated during ischemia and remains activated during early reperfusion. Inhibition of PKC activity post-ischemia impairs functional recovery, delays diastolic [Ca2+]i removal, and increases Ca2+ sensitivity of the contractile apparatus, resulting in impaired diastolic relaxation. Thus, post-ischemic PKC activity may serve to restore post-ischemic Ca2+ homeostasis and attenuate contractile protein calcium sensitivity during the period of post-ischemic [Ca2+]i overload.
KEYWORDS Protein kinases; Calcium (cellular); Contractile function; e-c coupling; Ischemia; Reperfusion
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