Reduced cardiac CapZ protein protects hearts against acute ischemia-reperfusion injury and enhances preconditioning

The Z-disc protein CapZ has historically been classified as a structural element, anchoring sarcomeric actin. Our previous work expanded its role to include signal transduction, as CapZ transgenic myofilaments are less sensitive to protein kinase C (PKC). Myocardial PKC has paradoxical effects, mediating both preconditioning and ischemia-reperfusion (IR) injury. Our objective was to determine how decreased CapZ affects IR injury and cardiac preconditioning. Mouse hearts were subjected to 20 min global ischemia and 60 min reperfusion. Some hearts were preconditioned with intermittent IR (IPC). Left ventricular function was assessed and myocardial tissue collected post-IR for molecular analysis and tissue staining. Post-ischemic function was significantly better and infarct size smaller in CapZ transgenic hearts, as compared to wildtype. IPC decreased IR damage in both wildtype and CapZ transgenic hearts, although CapZ transgenic hearts performed significantly better than wildtype. Immunoblotting revealed increased myofilament-associated PKC-alpha and -epsilon following IR in wildtype hearts, but no change in PKC-delta or -zeta. By contrast, post-IR myofilament-associated PKC-alpha was significantly higher in CapZ transgenic mice but the rise in PKC-epsilon was attenuated. Both PKC-delta and PKC-zeta decreased in CapZ transgenic myofilaments following IR. IPC increased myofilament-associated PKC-alpha, and -epsilon, while decreasing PKC-delta in wildtype hearts. Preconditioned CapZ IPC hearts showed attenuated increases in myofilament PKC-alpha and -epsilon, but also a significant decrease in myofilament PKC-delta and -zeta. These data demonstrate significant differences in post-IR myofilament PKC in untreated and preconditioned CapZ transgenic mice. CapZ reduction did not dramatically affect post-IR myofilament function, nor did preconditioning. These results demonstrate that CapZ deficiency decreases IR injury, while providing enhanced cardioprotection with IPC. The cardioprotected phenotype of CapZ transgenic mice is associated with an altered translocation of PKC-isoforms to cardiac myofilaments. (C) 2011 Elsevier Ltd. All rights reserved.