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dc.contributor.advisorHouser, Steven R.
dc.creatorZhang, Hongyu
dc.date.accessioned2020-11-05T16:15:54Z
dc.date.available2020-11-05T16:15:54Z
dc.date.issued2010
dc.identifier.other864884818
dc.identifier.urihttp://hdl.handle.net/20.500.12613/3919
dc.description.abstractMyocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined. Cardiac ryanodine receptor (RyR2) has been linked to cardiac arrhythmias and HF. It has been controversial that protein kinase A (PKA) hyperphosphorylation of the RyR2 at a single residue, Ser-2808 is a critical mediator of progressive cardiac dysfunction after MI. We developed two mouse models. In one model with beta2a (LTCC subunit) overexpression we could prevent depressed myocyte contractility after MI and use it to test the idea that preventing depression of myocyte Ca2+ handling defects could avert post MI cardiac pump dysfunction. In the other model, mice with Ser2808 in RyR2 replaced by alanine (S2808A) to prevent the phosphorylation at this site were used to determine whether loss of functional PKA phosphorylation site at Ser2808 could protect against cardiac dysfunction progression after MI. beta2a myocytes had increased Ca2+ current; contraction and Ca2+ transients (versus controls) and beta2a hearts had increased performance before MI. After MI, ventricular dilation, myocyte hypertrophy, and depressed cardiac pump function was greater in beta2a versus control hearts. There was also an increased rate of myocyte death in beta2a hearts after MI and survival was significantly reduced in these animals. We concluded that maintaining myocyte contractility after MI, by increasing Ca2+ influx, depresses rather than improves cardiac pump function. Baseline cardiac function was similar in wild type (WT) and RyR-S2808A mice before MI. After MI, there was no significant difference between WT and RyR-S2808A mice in EF and FS at 4 weeks. ICa-L € in WT and RyR-S2808A myocytes was not significantly different. There were significant ISO responses in all myocytes, and no appreciable differences in responsiveness were found. Contractions and Ca2+ transients were not significantly different in WT and RyR-S2808A myocytes after MI. In conclusion, preventing PKA phosphorylation of RyR at Ser2808 after MI does not protect the heart or its myocytes. The role of RyR phosphorylation at other sites on abnormal Ca2+ handling in diseased hearts is yet to be defined.
dc.format.extent168 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectBiology, Physiology
dc.subjectCardiac Function
dc.subjectCell Death
dc.subjectHeart Failure
dc.subjectMyocardial Infarction
dc.subjectMyocyte Contractility
dc.subjectRyanodine Receptor
dc.titleINCREASING MYOCYTE CONTRACTILITY EXACERBATES CARDIAC INJURY AND PUMP DYSFUNCTION AND ABLATION OF PHOSPHORYLATION
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberEguchi, Satoru
dc.contributor.committeememberSabri, Abdelkarim
dc.contributor.committeememberWang, Hong, 1956 September 19-
dc.contributor.committeememberChen, Xiongwen
dc.contributor.committeememberKoch, Walter J.
dc.description.departmentPhysiology
dc.relation.doihttp://dx.doi.org/10.34944/dspace/3901
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-11-05T16:15:54Z


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