The Effects of Decreased Cardiac CapZ Protein on the Myocardial Response to Stress
CapZ is an actin capping protein that locates at cardiac Z-discs and anchors sarcomeric actin . Transgenic (TG) mice overexpressing CapZ in cardiac myocytes develop a lethal cardiac hypertrophy , while a large reduction in CapZ protein causes severe myofibrillar disarray and death . However, a TG model that contains a modest reduction in cardiac CapZ protein levels is viable and is associated with decreased PKC-dependent regulation of myofilament function . Given the well known role of PKC in myocardial pathogenesis, the general aim of this thesis was to investigate how the modest reduction in CapZ protein affects cardiac function in models of cardiac stress. I found that PKC-translocation to cardiac myofilaments during cold cardioplegic arrest impairs myofilament activation, and that decreased cardiac CapZ protein disrupts this pathway and provides cardioprotective benefit. Using an in vivo model of ischemia-reperfusion (IR), I made the novel discovery that myofilament-associated PKC is altered during prolonged global ischemia, and found that a CapZ deficiency affects the translocation of PKC to myofilaments in a time-dependent manner. Furthermore, I found that TG mice deficient in CapZ demonstrate significant reductions in IR injury, while providing enhanced cardioprotection following ischemic preconditioning. The cardioprotected phenotype of CapZ-deficient TG mice is associated with altered translocation of several PKC-isoforms to cardiac myofilaments. Finally, having uncovered new information about the activation of protein phosphatase type 2A (PP2A) in IR, I investigated the role of CapZ in PP2A-dependent myofilament regulation. I found that reductions in CapZ may affect cardiac contractility by interrupting the association of PP2A with myofilaments. Together these findings expand the role of CapZ as a regulator of intracellular signaling molecules and demonstrate the novel ability of reduced CapZ to protect the heart against significant pathological threats.