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(Circulation Research. 2009;105:557.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Truncation of Titin’s Elastic PEVK Region Leads to Cardiomyopathy With Diastolic Dysfunction

Henk L. Granzier, Michael H. Radke, Jun Peng, Dirk Westermann, O. Lynne Nelson, Katharina Rost, Nicholas M.P. King, Qianli Yu, Carsten Tschöpe, Mark McNabb, Douglas F. Larson, Siegfried Labeit, Michael Gotthardt

From the Department of Physiology, Sarver Molecular Cardiovascular Research Program (H.G., N.K.) and the Sarver Heart Center and Department of Surgery, College of Medicine (Q.Y., D.L.), University of Arizona, Tucson; Neuromuscular and Cardiovascular Cell Biology (M.R., K.R., M.G.), Max-Delbrück-Center for Molecular Medicine (MDC), Berlin-Buch, Germany; the Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology (J.P., M.M., M.G.) and the Department of Veterinary Clinical Sciences (O.N.), Washington State University, Pullman; the Department of Cardiology (D.W., C.T.), Campus Benjamin Franklin, Berlin, Germany; and the Medical Faculty Mannheim (S.L.), Mannheim University, Germany.

Correspondence to Michael Gotthardt, Max-Delbrück-Center for Molecular Medicine Berlin-Buch, Robert Rössle Str. 10, 13125 Berlin, Germany. E-mail gotthardt{at}mdc-berlin.de

Rationale: The giant protein titin plays key roles in myofilament assembly and determines the passive mechanical properties of the sarcomere. The cardiac titin molecule has 2 mayor elastic elements, the N2B and the PEVK region. Both have been suggested to determine the elastic properties of the heart with loss of function data only available for the N2B region.

Objective: The purpose of this study was to investigate the contribution of titin’s proline–glutamate–valine–lysine (PEVK) region to biomechanics and growth of the heart.

Methods and Results: We removed a portion of the PEVK segment (exons 219 to 225; 282 aa) that corresponds to the PEVK element of N2B titin, the main cardiac titin isoform. Adult homozygous PEVK knockout (KO) mice developed diastolic dysfunction, as determined by pressure-volume loops, echocardiography, isolated heart experiments, and muscle mechanics. Immunoelectron microscopy revealed increased strain of the N2B element, a spring region retained in the PEVK-KO. Interestingly, the PEVK-KO mice had hypertrophied hearts with an induction of the hypertrophy and fetal gene response that includes upregulation of FHL proteins. This contrasts the cardiac atrophy phenotype with decreased FHL2 levels that result from the deletion of the N2B element.

Conclusions: Titin’s PEVK region contributes to the elastic properties of the cardiac ventricle. Our findings are consistent with a model in which strain of the N2B spring element and expression of FHL proteins trigger cardiac hypertrophy. These novel findings provide a molecular basis for the future differential therapy of isolated diastolic dysfunction versus more complex cardiomyopathies.

Key Words: diastole • connectin • hypertrophy • compliance • FHL