BACKGROUND: Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of beta-amyloid impair cell function and lead to cell death. METHODS AND RESULTS: We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca(2+) homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. CONCLUSIONS: On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca(2+) handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.
BACKGROUND:Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of beta-amyloid impair cell function and lead to cell death. METHODS AND RESULTS: We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca(2+) homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. CONCLUSIONS: On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca(2+) handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.
Authors: Rakez Kayed; Elizabeth Head; Jennifer L Thompson; Theresa M McIntire; Saskia C Milton; Carl W Cotman; Charles G Glabe Journal: Science Date: 2003-04-18 Impact factor: 47.728
Authors: Sanda Despa; Kenneth B Margulies; Le Chen; Anne A Knowlton; Peter J Havel; Heinrich Taegtmeyer; Donald M Bers; Florin Despa Journal: Circ Res Date: 2012-01-24 Impact factor: 17.367
Authors: Khaushik Subramanian; Davide Gianni; Cristina Balla; Gabriele Egidy Assenza; Mugdha Joshi; Marc J Semigran; Thomas E Macgillivray; Jennifer E Van Eyk; Giulio Agnetti; Nazareno Paolocci; James R Bamburg; Pankaj B Agrawal; Federica Del Monte Journal: J Am Coll Cardiol Date: 2015-03-31 Impact factor: 24.094