Cardiomyocyte Autophagy is Induced by Protein Aggregation in Heart Disease

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Title: Cardiomyocyte Autophagy is Induced by Protein Aggregation in Heart Disease
Author: Tannous, Paul
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 .
URI: http : / /hdl .handle .net /2152 .5 /245
Date: 2009-06-19


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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