Cardiomyocyte Autophagy is Induced by Protein Aggregation in Heart Disease

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dc.contributor.advisor Hill , Joseph A . en
dc.creator Tannous , Paul en
dc.date.accessioned 2010 -07 -12T17 :16 :39Z en
dc.date.accessioned 2014 -02 -19T22 :00 :33Z
dc.date.available 2010 -07 -12T17 :16 :39Z en
dc.date.available 2014 -02 -19T22 :00 :33Z
dc.date.issued 2009 -06 -19 en
dc.identifier.other 754799915 en
dc.identifier.uri http : / /hdl .handle .net /2152 .5 /245 en
dc.description.abstract Autophagy is associated with diverse forms of myocardial stress . When I initiated my studies activators of this pathway had not been identified in the heart , nor was it clear weather autophagy is an adaptive or maladaptive response in the stressed myocardium . My initial research focused on autophagy in hypertension -induced heart failure , the most common cardiovascular disease in Western nations . Early evidence demonstrated generation of reactive oxygen species , protein damage , and protein aggregation in the acute period of pressure overload . Given the simultaneous presence of autophagosomes and aggregates , and autophagy's role in bulk degradation , I postulated these events were mechanistically linked . I designed experiments to test the hypotheses that protein aggregates are activators of autophagy in the heart , and that autophagy functions in aggregate clearance . Here I report novel findings that link pressure overload -induced protein aggregation to increased cardiomyocyte autophagy . Specifically , in the pressure -stressed ventricle 1 ) generation of reactive oxygen species is an early pathological event , 2 ) there is extensive protein aggregation with higher -order processing into aggresomes , 3 ) protein aggregation induces cardiomyocyte autophagy , and 4 ) in this setting autophagy functions in its role as a mechanism of bulk protein degradation . These findings are the first to demonstrate proteinopathy of non -genetic etiology contributes to hypertension -induced heart failure and that protein aggregates are robust activators of cardiomyocyte autophagy . To directly address the role of autophagy in cardiomyocyte clearance of toxic protein species , I turned my attention to CryABR120G -induced desmin -related cardiomyopathy (DRCM ) , an aggregate -associated disease with autosomal dominant inheritance . My studies demonstrated that 1 ) autophagy is activated by CryABR120G -induced protein aggregation , 2 ) aggregate formation is inversely proportional to the degree of autophagic activity and 3 ) blunting autophagy accelerates pathological myocardial remodeling and the onset of heart failure . Extending this work to clinical medicine , we observed increased autophagy in the skeletal muscle from patients with desmin -related skeletal myopathy . Cumulatively these data are the first to demonstrate autophagy is induced in DRCM and functions as a protective cellular response . These findings suggest autophagy is a pathway amenable to therapeutic intervention in patients suffering from myofibrillar myopathy , a disease class for which there are limited therapeutic options . en
dc.format.medium Electronic en
dc.format.mimetype application /pdf en
dc.language.iso en en
dc.subject Myocytes , Cardiac en
dc.subject Heart Disease en
dc.subject Autophagy en
dc.subject Proteins en
dc.title Cardiomyocyte Autophagy is Induced by Protein Aggregation in Heart Disease en
dc.type.genre dissertation en
dc.type.material Text en
thesis.degree.name Doctor of Philosophy en
thesis.degree.level Ph .D en
thesis.degree.discipline Integrative Biology en
thesis.degree.grantor Graduate School of Biomedical Sciences en
thesis.degree.department en
dc.format.digitalOrigin born digital en
thesis.date.available 2011 -06 -19 en

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Cardiomyocyte Autophagy is Induced by Protein Aggregation in Heart Disease. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /245 .

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