Year: 2008
Type: article
Abstract: BACKGROUND: To determine whether soluble preamyloid oligomers (PAOs) are toxic when expressed internally in the cardiomyocyte, we tested the hypothesis that cardiomyocyte-restricted expression and accumulation of a known PAO is cytotoxic and sufficient to cause heart failure. METHODS AND RESULTS: Intracellular PAOs, the entities believed to cause toxicity in many neurodegenerative diseases, have been observed in cardiomyocytes derived from mouse and human heart failure samples. Long (>50) polyglutamine (PQ) repeats form PAOs and cause neurotoxicity in Huntington disease and other neurodegenerative diseases, whereas shorter PQ peptides are benign. We created transgenic mice in which cardiomyocyte-autonomous expression of an 83 residue-long PQ repeat (PQ83) or a non-amyloid-forming peptide of 19 PQ repeats (PQ19) as a nonpathological control was expressed. A PQ83 line with relatively low levels of expression was generated, along with a PQ19 line that expressed approximately 9-fold the levels observed in the PQ83 line. Hearts expressing PQ83 exhibited reduced cardiac function and dilation by 5 months, and all mice died by 8 months, whereas PQ19 mice had normal cardiac function, morphology, and life span. PQ83 protein accumulated within aggresomes with PAO-specific staining. The PQ83 hearts showed increased autophagosomal and lysosomal content but also showed markers of necrotic death, including inflammatory cell infiltration and increased sarcolemmal permeability. CONCLUSIONS: The data confirm the hypothesis that expression of an exogenous PAO-forming peptide is toxic to cardiomyocytes and is sufficient to cause cardiomyocyte loss and heart failure in a murine model.
Source: Circulation
Institution: Cincinnati Children's Hospital Medical Center
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
Awards: G1071590312, G1106861790, SCCOR in Pediatric Heart Development and Disease, Signaling Processes Underlying Cardiovascular Function, G268288826, Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation, The Role of Apoptosis in CryABR120G Heart Failure, G4894314261, G6914319556, Genetic and Molecular Signaling in Heart Failure, Cardiomyocyte Toxicity and Heart Failure in Desmin Related Cardiomyopathy, Pulmonary Development and Disease Pathogenesis Training Program
OpenAlex ID: W2061301580