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 Ca(2+)- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca(2+)- 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.
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, Ohio; Sakima.smith@osumc.edu.
Sakima A
SA
Smith
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio;
Langston D
LD
Hughes
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, Columbus, Ohio;
Crystal F
CF
Kline
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, Columbus, Ohio;
Amber N
AN
Kempton
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, Columbus, Ohio;
Lisa E
LE
Dorn
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, Columbus, Ohio;
Jerry
J
Curran
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, Columbus, Ohio;
Michael
M
Makara
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, Columbus, Ohio;
Tyler R
TR
Webb
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, Columbus, Ohio;
Patrick
P
Wright
Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany; and.
Niels
N
Voigt
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, Ohio;
Philip F
PF
Binkley
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, Columbus, Ohio;
Paul M L
PM
Janssen
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio;
Ahmet
A
Kilic
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; College of Pharmacy, The Ohio State University, Columbus, Ohio;
Cynthia A
CA
Carnes
Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany; and.
Dobromir
D
Dobrev
Department of Neuroscience, Baylor College of Medicine, Houston, Texas.
Matthew N
MN
Rasband
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio;
Thomas J
TJ
Hund
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, Columbus, Ohio;
Peter J
PJ
Mohler
D000328:Adult; D000368:Aged; D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004285:Dogs; D015536:Down-Regulation; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D059748:Proteolysis; D015398:Signal Transduction; D013049:Spectrin / Q000378:metabolism*; D013318:Stroke Volume; D016277:Ventricular Function, Left
C498994:ANK2 protein, human; D017487:Ankyrins; C495133:SPTBN2 protein, human; C000595041:SPTBN2 protein, mouse; D013049:Spectrin; D002154:Calpain; D002118:Calcium
arrhythmias/cardiac; cytoskeleton; ion channels