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Increased myocardial stiffness due to cardiac titin isoform switching in a mouse model of volume overload limits eccentric remodeling.

Abstract
We investigated the cellular and molecular mechanisms of diastolic dysfunction in pure volume overload induced by aortocaval fistula (ACF) surgery in the mouse. Four weeks of volume overload resulted in significant biventricular hypertrophy; protein expression analysis in left ventricular (LV) tissue showed a marked decrease in titin's N2BA/N2B ratio with no change in phosphorylation of titin's spring region. Titin-based passive tensions were significantly increased; a result of the decreased N2BA/N2B ratio. Conscious echocardiography in ACF mice revealed eccentric remodeling and pressure volume analysis revealed systolic dysfunction: reductions in ejection fraction (EF), +dP/dt, and the slope of the end-systolic pressure volume relationships (ESPVR). ACF mice also had diastolic dysfunction: increased LV end-diastolic pressure and reduced relaxation rates. Additionally, a decrease in the slope of the end diastolic pressure volume relationship (EDPVR) was found. However, correcting for altered geometry of the LV normalized the change in EDPVR and revealed, in line with our skinned muscle data, increased myocardial stiffness in vivo. ACF mice also had increased expression of the signaling proteins FHL-1, FHL-2, and CARP that bind to titin's spring region suggesting that titin stiffening is important to the volume overload phenotype. To test this we investigated the effect of volume overload in the RBM20 heterozygous (HET) mouse model, which exhibits reduced titin stiffness. It was found that LV hypertrophy was attenuated and that LV eccentricity was exacerbated. We propose that pure volume overload induces an increase in titin stiffness that is beneficial and limits eccentric remodeling.
AuthorsKirk R Hutchinson, Chandra Saripalli, Charles S Chung, Henk Granzier
JournalJournal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 79 Pg. 104-14 (Feb 2015) ISSN: 1095-8584 [Electronic] England
PMID25450617 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • Collagen Type I
  • Connectin
  • Protein Isoforms
Topics
  • Animals
  • Arteriovenous Fistula (diagnostic imaging, metabolism, pathology, physiopathology)
  • Blood Pressure
  • Blotting, Western
  • Cardiomegaly (diagnostic imaging, metabolism, pathology, physiopathology)
  • Collagen Type I (metabolism)
  • Connectin (metabolism)
  • Diastole
  • Disease Models, Animal
  • Electrocardiography
  • Extracellular Matrix (metabolism)
  • Heart Ventricles (diagnostic imaging, metabolism, pathology, physiopathology)
  • Male
  • Mice, Inbred C57BL
  • Myocardium (metabolism, pathology)
  • Pressure
  • Protein Isoforms (metabolism)
  • Sarcomeres (metabolism)
  • Systole
  • Ultrasonography
  • Ventricular Remodeling

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