TY - JOUR
T1 - Hypothyroidism leads to increased collagen-based stiffness and re-expression of large cardiac titin isoforms with high compliance
AU - Wu, Yiming
AU - Peng, Jun
AU - Campbell, Kenneth B.
AU - Labeit, Siegfried
AU - Granzier, Henk
N1 - Funding Information:
We are grateful to Mr. McNabb for microscopy, Ms. Zhou for microarray analysis, Ms. Simpson for isolated heart experiments and to Ms. Luo and Ms. Benoist for electrophoresis. Supported by NIH grant HL61497 (HG) and AHA grant 0435241N (YW).
PY - 2007/1
Y1 - 2007/1
N2 - 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.
AB - 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.
KW - Collagen
KW - Connectin
KW - Diastolic stiffness
KW - Extra cellular matrix
KW - Fetal cardiac isoforms
KW - Passive stiffness
KW - Titin
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U2 - 10.1016/j.yjmcc.2006.09.017
DO - 10.1016/j.yjmcc.2006.09.017
M3 - Article
C2 - 17069849
AN - SCOPUS:33845605523
SN - 0022-2828
VL - 42
SP - 186
EP - 195
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 1
ER -