| Molecular mechanism of the E99K mutation in cardiac actin (ACTC Gene) that causes apical hypertrophy in man and mouse. | |
| | |
MedLine Citation:
|
PMID: 21622575 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca(2+) sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca(2+) sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to β-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca(2+) sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice. |
| | |
Authors:
|
Weihua Song; Emma Dyer; Daniel J Stuckey; O'Neal Copeland; Man-Ching Leung; Christopher Bayliss; Andrew Messer; Ross Wilkinson; Jordi Lopez Tremoleda; Michael D Schneider; Sian E Harding; Charles S Redwood; Kieran Clarke; Kristen Nowak; Lorenzo Monserrat; Dominic Wells; Steven B Marston |
Related Documents
:
|
15821835 - Effect of flaxseed consumption on blood pressure, serum lipids, hemopoietic system and ... 11403505 - Effect of coronary risk factors on arterial compensatory enlargement in japanese middle... 22433315 - Cardiovascular effects of antidiabetic agents: focus on blood pressure effects of incre... 8428785 - Altered blood pressure during sleep in normotensive subjects with type i diabetes. 1019165 - The use of saralasin in the recognition of angiotensinogenic hypertension. 2239665 - Are ioxaglate and iopamidol equally safe and well tolerated in cardiac angiography? a r... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-05-26 |
Journal Detail:
|
Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Aug |
Date Detail:
|
Created Date: 2011-08-01 Completed Date: 2011-10-10 Revised Date: 2013-05-24 |
Medline Journal Info:
|
Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
|
Languages: eng Pagination: 27582-93 Citation Subset: IM |
Affiliation:
|
National Heart and Lung Institute, Imperial College London, London SW32 6LY, United Kingdom. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Actins
/
genetics* Animals Cardiomegaly / genetics* Female Humans Male Mice Mice, Transgenic Mutation* |
| Grant Support | |
ID/Acronym/Agency:
|
//British Heart Foundation |
| Chemical | |
Reg. No./Substance:
|
0/Actins |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Skeletal muscle differentiation and fusion are regulated by the BAR-containing Rho-GTPase-activating...
Next Document: The Ets factor Etv1 interacts with Tpit protein for pituitary pro-opiomelanocortin (POMC) gene trans...