The Effects of Decreased Cardiac CapZ Protein on the Myocardial Response to Stress

The Atrium, University of Guelph Institutional Repository

The Effects of Decreased Cardiac CapZ Protein on the Myocardial Response to Stress

Show simple item record

dc.contributor.advisor Pyle, W. Glen
dc.contributor.author Yang, Feng Hua
dc.date 2012-03-28
dc.date.accessioned 2012-04-18T20:36:33Z
dc.date.available 2012-04-18T20:36:33Z
dc.date.issued 2012-04-18
dc.identifier.uri http://hdl.handle.net/10214/3506
dc.description.abstract CapZ is an actin capping protein that locates at cardiac Z-discs and anchors sarcomeric actin [1]. Transgenic (TG) mice overexpressing CapZ in cardiac myocytes develop a lethal cardiac hypertrophy [2], while a large reduction in CapZ protein causes severe myofibrillar disarray and death [2]. 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 [3]. 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. en_US
dc.description.sponsorship Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Ontario (HSFO), Heart and Stroke Foundation of Canada (HSFC), The Premier's Research Excellence Award (PREA), Ontario Graduate Scholarship Program (OGS). en_US
dc.language.iso en en_US
dc.subject Cardiac function en_US
dc.subject Ischemia-reperfusion Injury en_US
dc.subject Myofilaments en_US
dc.subject Protein kinase C en_US
dc.subject CapZ en_US
dc.title The Effects of Decreased Cardiac CapZ Protein on the Myocardial Response to Stress en_US
dc.type Thesis en_US
dc.degree.programme Biomedical Sciences en_US
dc.degree.name Doctor of Philosophy en_US
dc.degree.department Department of Biomedical Sciences en_US


Files in this item

Files Size Format View Description
CapZ and cardiac stress-FY-Apr18.pdf 3.600Mb PDF View/Open FY_CapZ

This item appears in the following Collection(s)

Show simple item record

Search the Atrium


Advanced Search

Browse

My Account