Abstract |
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant genetic disorder linked to numerous mutations in the sarcomeric proteins. The clinical presentation of FHC is highly variable, but it is a major cause of sudden cardiac death in young adults with no specific treatments. We tested the hypothesis that early intervention in Ca(2+) regulation may prevent pathological hypertrophy and improve cardiac function in a FHC displaying increased myofilament sensitivity to Ca(2+) and diastolic dysfunction. A transgenic (TG) mouse model of FHC with a mutation in tropomyosin at position 180 was employed. Adenoviral-Serca2a (Ad.Ser) was injected into the left ventricle of 1-day-old non-transgenic (NTG) and TG mice. Ad.LacZ was injected as a control. Serca2a protein expression was significantly increased in NTG and TG hearts injected with Ad.Ser for up to 6 weeks. Compared to TG-Ad.LacZ hearts, the TG-Ad.Ser hearts showed improved whole heart morphology. Moreover, there was a significant decline in ANF and β-MHC expression. Developed force in isolated papillary muscle from 2- to 3-week-old TG-Ad.Ser hearts was higher and the response to isoproterenol (ISO) improved compared to TG-Ad.LacZ muscles. In situ hemodynamic measurements showed that by 3 months the TG-Ad.Ser hearts also had a significantly improved response to ISO compared to TG-Ad.LacZ hearts. The present study strongly suggests that Serca2a expression should be considered as a potential target for gene therapy in FHC. Moreover, our data imply that development of FHC can be successfully delayed if therapies are started shortly after birth.
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Authors | James R Peña, Ariani C Szkudlarek, Chad M Warren, Lynley S Heinrich, Robert D Gaffin, Ganapathy Jagatheesan, Federica del Monte, Roger J Hajjar, Paul H Goldspink, R John Solaro, David F Wieczorek, Beata M Wolska |
Journal | Journal of molecular and cellular cardiology
(J Mol Cell Cardiol)
Vol. 49
Issue 6
Pg. 993-1002
(Dec 2010)
ISSN: 1095-8584 [Electronic] England |
PMID | 20854827
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2010 Elsevier Ltd. All rights reserved. |
Chemical References |
- Calcium-Binding Proteins
- Protein Isoforms
- phospholamban
- Atrial Natriuretic Factor
- Sarcoplasmic Reticulum Calcium-Transporting ATPases
- Myosin Heavy Chains
- Isoproterenol
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Topics |
- Actin Cytoskeleton
(drug effects, metabolism)
- Adenoviridae
(genetics)
- Animals
- Animals, Newborn
- Atrial Natriuretic Factor
(metabolism)
- Calcium-Binding Proteins
(metabolism)
- Cardiomyopathy, Hypertrophic, Familial
(physiopathology, therapy)
- Gene Transfer Techniques
- Genetic Therapy
- Heart Function Tests
- Hemodynamics
(drug effects)
- Humans
- Injections
- Isoproterenol
(pharmacology)
- Mice
- Mice, Transgenic
- Myocardial Contraction
(drug effects)
- Myosin Heavy Chains
(metabolism)
- Phosphorylation
(drug effects)
- Protein Isoforms
(metabolism)
- Rabbits
- Sarcoplasmic Reticulum Calcium-Transporting ATPases
(genetics, therapeutic use)
- Ventricular Remodeling
(drug effects, physiology)
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