Dysfunction of the [Beta]^sub 2^-spectrin-based pathway in human heart failure

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