Dysfunction of the β₂-spectrin-based pathway in human heart failure

β₂-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of β₂-spectrin for vertebrate function is illustrated by dysfunction of β₂-spectrin-based pathways in disease. Recently, defects in β₂-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of β₂-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that β₂-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, β₂-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, β₂-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 β₂-spectrin protein levels. Mechanistically, we identify that β₂-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca²⁺-and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca²⁺-and calpain-dependent loss of β₂-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that β₂-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca^2+-and calpain-dependent proteolysis.