Dysfunction of the ß2-spectrin-based pathway in human heart failure.
Am J Physiol Heart Circ Physiol
; 310(11): H1583-91, 2016 06 01.
Article
em En
| MEDLINE
| ID: mdl-27106045
ABSTRACT
ß2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of ß2-spectrin for vertebrate function is illustrated by dysfunction of ß2-spectrin-based pathways in disease. Recently, defects in ß2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of ß2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that ß2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, ß2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, ß2-spectrin levels were significantly decreased in left ventricle of ischemic- and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced ß2-spectrin protein levels. Mechanistically, we identify that ß2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca(2+)- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca(2+)- and calpain-dependent loss of ß2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that ß2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca(2+)- and calpain-dependent proteolysis.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article