|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | |||||
First published online 2 August 2005
doi: 10.1242/jcs.02492
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Research Article |
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL 33136, USA
* Author for correspondence (e-mail: dszczesna{at}med.miami.edu)
Accepted 13 May 2005
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease caused by mutations in all of the major sarcomeric proteins, including the ventricular myosin regulatory light-chain (RLC). The E22K-RLC mutation has been associated with a rare variant of cardiac hypertrophy defined by mid-left ventricular obstruction due to papillary muscle hypertrophy. This mutation was later found to cause ventricular and septal hypertrophy. We have generated transgenic (Tg) mouse lines of myc-WT (wild type) and myc-E22K mutant of human ventricular RLC and have examined the functional consequences of this FHC mutation in skinned cardiac-muscle preparations. In longitudinal sections of whole mouse hearts stained with hematoxylin and eosin, the E22K-mutant hearts of 13-month-old animals showed signs of inter-ventricular septal hypertrophy and enlarged papillary muscles with no filament disarray. Echo examination did not reveal evidence of cardiac hypertrophy in Tg-E22K mice compared to Tg-WT or Non-Tg hearts. Physiological studies utilizing skinned cardiac-muscle preparations showed an increase by
pCa50
0.1 in Ca2+ sensitivity of myofibrillar ATPase activity and force development in Tg-E22K mice compared with Tg-WT or Non-Tg littermates. Our results suggest that E22K-linked FHC is mediated through Ca2+-dependent events. The FHC-mediated structural perturbations in RLC that affect Ca2+ binding properties of the mutated myocardium are responsible for triggering the abnormal function of the heart that in turn might initiate a hypertrophic process and lead to heart failure.
Key words: Hypertrophic cardiomyopathy, Myosin regulatory light-chain, Muscles, Physiology
![]()
CiteULike
Complore
Connotea
Del.icio.us
Digg
Reddit
Technorati
Twitter What's this?
Related articles in JCS:
This article has been cited by other articles:
![]() |
W. G. L. Kerrick, K. Kazmierczak, Y. Xu, Y. Wang, and D. Szczesna-Cordary Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice FASEB J, March 1, 2009; 23(3): 855 - 865. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Morimoto Sarcomeric proteins and inherited cardiomyopathies Cardiovasc Res, March 1, 2008; 77(4): 659 - 666. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Szczesna-Cordary, M. Jones, J. R. Moore, J. Watt, W. G. L. Kerrick, Y. Xu, Y. Wang, C. Wagg, and G. D. Lopaschuk Myosin regulatory light chain E22K mutation results in decreased cardiac intracellular calcium and force transients FASEB J, December 1, 2007; 21(14): 3974 - 3985. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Dumka, J. Talent, I. Akopova, G. Guzman, D. Szczesna-Cordary, and J. Borejdo E22K mutation of RLC that causes familial hypertrophic cardiomyopathy in heterozygous mouse myocardium: effect on cross-bridge kinetics Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2098 - H2106. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. E. Stelzer, J. R. Patel, and R. L. Moss Acceleration of Stretch Activation in Murine Myocardium due to Phosphorylation of Myosin Regulatory Light Chain J. Gen. Physiol., August 28, 2006; 128(3): 261 - 272. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. D. Epstein and J. S. Davis When Is a Fly in the Ointment a Solution and not a Problem? Circ. Res., May 12, 2006; 98(9): 1110 - 1112. [Full Text] [PDF] |
||||