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

dc.contributor.advisorPyle, W. Glen
dc.contributor.authorYang, Feng Hua
dc.date.accessioned2012-04-18T20:36:33Z
dc.date.available2012-04-18T20:36:33Z
dc.date.copyright2012-04
dc.date.created2012-03-28
dc.date.issued2012-04-18
dc.degree.departmentDepartment of Biomedical Sciencesen_US
dc.degree.grantorUniversity of Guelphen_US
dc.degree.nameDoctor of Philosophyen_US
dc.degree.programmeBiomedical Sciencesen_US
dc.description.abstractCapZ 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.sponsorshipCanadian Institutes of Health Research
dc.description.sponsorshipHeart and Stroke Foundation of Ontario
dc.description.sponsorshipHeart and Stroke Foundation of Canada
dc.description.sponsorshipPremier's Research Excellence Award
dc.description.sponsorshipOntario Graduate Scholarship
dc.identifier.urihttp://hdl.handle.net/10214/3506
dc.language.isoenen_US
dc.publisherUniversity of Guelphen_US
dc.rights.licenseAll items in the Atrium are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectCardiac functionen_US
dc.subjectIschemia-reperfusion Injuryen_US
dc.subjectMyofilamentsen_US
dc.subjectProtein kinase Cen_US
dc.subjectCapZen_US
dc.titleThe Effects of Decreased Cardiac CapZ Protein on the Myocardial Response to Stressen_US
dc.typeThesisen_US

Files

Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
CapZ_and_cardiac_stress-FY-Apr18.pdf
Size:
3.6 MB
Format:
Adobe Portable Document Format
Description:
FY_CapZ
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
317 B
Format:
Item-specific license agreed upon to submission
Description: