Document Detail

Hypothyroidism leads to increased collagen-based stiffness and re-expression of large cardiac titin isoforms with high compliance.
MedLine Citation:
PMID:  17069849     Owner:  NLM     Status:  MEDLINE    
Because long-term hypothyroidism results in diastolic dysfunction, we investigated myocardial passive stiffness in hypothyroidism and focused on the possible role of titin, an important determinant of diastolic stiffness. A rat model of hypothyroidism was used, obtained by administering propylthiouracil (PTU) for times that varied from 1 month (short-term) to 4 months (long-term). Titin expression was determined by transcript analysis, gel electrophoresis and immunoelectron microscopy. Diastolic function was measured at the isolated heart, skinned muscle, and cardiac myocyte levels. We found that hypothyroidism resulted in expression of a large titin isoform, the abundance of which gradually increased with time to become the most dominant isoform in long-term hypothyroid rats. This isoform co-migrates on high-resolution gels with fetal cardiac titin. Transcript analysis on myocardium of long-term PTU rats, provided evidence for expression of additional PEVK and Ig domain exons, similar to what has been described in fetal myocardium. Consistent with the expression of a large titin isoform, titin-based restoring and passive forces were significantly reduced in single cardiac myocytes and muscle strips of long-term hypothyroid rats. Overall muscle stiffness and LV diastolic wall stiffness were increased, however, due to increased collagen-based stiffness. We conclude that long term hypothyroidism triggers expression of a large cardiac titin isoform and that the ensuing reduction in titin-based passive stiffness functions as a compensatory mechanism to reduce LV wall stiffness.
Yiming Wu; Jun Peng; Kenneth B Campbell; Siegfried Labeit; Henk Granzier
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-10-27
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  42     ISSN:  0022-2828     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2006-12-25     Completed Date:  2007-02-27     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  186-95     Citation Subset:  IM    
Department VCAPP, Washington State University, Pullman, WA 99164-6520, USA.
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MeSH Terms
Collagen / chemistry,  metabolism*
Gene Expression Profiling
Heart Ventricles / physiopathology
Hypothyroidism / genetics,  metabolism*,  physiopathology
Muscle Proteins / chemistry,  genetics,  metabolism*
Myocardial Contraction
Myocytes, Cardiac / metabolism*
Oligonucleotide Array Sequence Analysis
Protein Isoforms / chemistry,  genetics,  metabolism
Rats, Sprague-Dawley
Grant Support
Reg. No./Substance:
0/Muscle Proteins; 0/Protein Isoforms; 0/Ttn protein, rat; 9007-34-5/Collagen

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