The role of CapZ in PKC signalling, metabolic acidosis, and oxidative stress
Cardiac Z-disks actively initiate, regulate, and modulate myofilamet function directly, and by controlling intracellular signalling by anchoring intracellular messengers. Small reductions in the Z-disk protein 'CapZ' improves cardiac muscle contractility and impairs PKC-dependent inhibition of myofilaments. The mechanism by which CapZ mediates its effects is unknown. This research tested the hypothesis that CapZ mediates control over PKC signalling by altering the PKC activation co-factors PIP2 and RACK1. It was found that PIP2 and RACK1 were associated with cardiac myofilaments, that there was a selective reduction in myofilament PIP2 mediated by CapZ extraction, but CapZ reduction had no effect on RACK1 protein levels. Previous work has shown that even when PKC is activated with exogenous co-factors, cardiac myofilaments have a blunted response. To determine if CapZ removal alters the myofilament response to modifications (stressors), we examined the impact of acidosis and oxidation on CapZ-deficient myofilaments. The extraction of CapZ was unable to improve the myofilament dysfunction generated by metabolic acidosis, but CapZ deficient myofilaments were more resistant to oxidative stress than control myofilaments. These results provide insight into the mechanisms by which CapZ regulates cardiac myofilaments, and the role of CapZ in PKC signalling.