title: Deposition of nonsarcomeric alpha-actinin in cardiomyocytes from patients with dilated cardiomyopathy or chronic pressure overload.
abstract: Nonsarcomeric alpha-actinin (ACTN-1)-positive clusters have been detected in human myocardium structurally jeopardized by dilated cardiomyopathy, hypertrophy due to aortic stenosis, or chronic hibernation, but have never been detected in normal tissue. To systematically investigate these clusters, immunohistochemistry, electron microscopy, Northern blot and Western blot were performed in human myocardium, isolated rat cardiomyocytes and rabbit smooth muscle cells. ACTN-1-positive clusters were localized in the perinuclear area of cardiomyocytes surrounded by rough endoplasmic reticulum. Quantification of structures containing ACTN-1 showed that it was present in up to 10% of all myocytes in 60% of aortic stenosis patients with severely reduced ejection fraction and in 70% of patients with dilated cardiomyopathy, exclusively in myocytes from hearts with structural degeneration and reduced function. Ultrastructurally, clusters of medium electron density corresponding to the confocal microscopic accumulations were observed in the same tissue samples. The messenger RNA of ACTN-1 was unchanged compared with controls, but a Western blot revealed that the protein was significantly elevated in failing hearts. Because membranes of the endoplasmic reticulum surround the clusters, it was concluded that in the presence of undisturbed transcription, a post-translational malfunction of ACTN-1 glycosylation might lead to storage of this protein. Autophagic and ischemic cell death were observed, but a possible toxic effect of this storage product was excluded because markers of cell death rarely colocalized with ACTN-1. The occurrence of ACTN-1-positive clusters, however, appears to be a useful marker for structural degeneration in failing myocardium.
authors.affiliation: Kerckhoff Clinic;
authors.forename: Stefan
authors.initials: S
authors.lastname: Hein
authors.forename: Tim
authors.initials: T
authors.lastname: Block
authors.forename: René
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Sawa
authors.initials: S
authors.lastname: Kostin
authors.forename: Thomas
authors.initials: T
authors.lastname: Scheffold
authors.forename: Thomas
authors.initials: T
authors.lastname: Kubin
authors.forename: Wolf-Peter
authors.initials: WP
authors.lastname: Klövekorn
authors.forename: Jutta
authors.initials: J
authors.lastname: Schaper