Document Detail

Partial restoration of cardio-vascular defects in a rescued severe model of spinal muscular atrophy.
MedLine Citation:
PMID:  22285962     Owner:  NLM     Status:  MEDLINE    
Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death. Loss of a gene called Survival Motor Neuron 1 (SMN1) and, as a result, reduced levels of the Survival Motor Neuron (SMN) protein leads to SMA development. SMA is characterized by the loss of functional motor neurons in the spinal cord. However, accumulating evidence suggests the contribution of other organs to the composite SMA phenotype and disease progression. A growing number of congenital heart defects have been identified in severe SMA patients. Consistent with the clinical cases, we have recently identified developmental and functional heart defects in two SMA mouse models, occurring at embryonic stage in a severe SMA model and shortly after birth in a less severe model (SMN∆7). Our goal was to examine the late stage cardiac abnormalities in untreated SMN∆7 mice and to determine whether gene replacement therapy restores cardiac structure/function in rescued SMN∆7 model. To reveal the extent of the cardiac structural/functional repair in the rescued mice, we analyzed the heart of untreated and treated SMN∆7 model using self-complementary Adeno-associated virus (serotype 9) expressing the full-length SMN cDNA. We examined the characteristics of the heart failure such as remodeling, fibrosis, oxidative stress, and vascular integrity in both groups. Our results clearly indicate that fibrosis, oxidative stress activation, vascular remodeling, and a significant decrease in the number of capillaries exist in the SMA heart. The cardiac structural defects were improved drastically in the rescued animals, however, the level of impairment was still significant compared to the age-matched wildtype littermates. Furthermore, functional analysis by in vivo cardiac magnetic resonance imaging (MRI) revealed that the heart of the treated SMA mice still exhibits functional defects. In conclusion, cardiac abnormalities are only partially rescued in post-birth treated SMA animals and these abnormalities may contribute to the premature death of vector-treated SMA animals with seemingly rescued motor function but an average life span of less than 70 days as reported in several studies.
Monir Shababi; Javad Habibi; Lixin Ma; Jacqueline J Glascock; James R Sowers; Christian L Lorson
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-17
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  52     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-16     Completed Date:  2012-08-07     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1074-82     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
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MeSH Terms
Angiotensin II / metabolism
Coronary Vessels / metabolism,  physiology
Disease Models, Animal
Genetic Therapy*
Heart / physiopathology
Heart Ventricles / abnormalities*,  pathology,  physiopathology
Mice, Knockout
Muscular Atrophy, Spinal / metabolism,  pathology,  therapy*
NADPH Oxidase / metabolism
Oxidative Stress
Receptor, Angiotensin, Type 1 / metabolism
Spinal Cord / enzymology,  metabolism
Survival of Motor Neuron 1 Protein / genetics*
Ventricular Remodeling / genetics
Grant Support
R01 HL073101/HL/NHLBI NIH HHS; R01 HL073101-08/HL/NHLBI NIH HHS; R01 HL107910/HL/NHLBI NIH HHS; R01 HL107910-01/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Receptor, Angiotensin, Type 1; 0/Smn1 protein, mouse; 0/Survival of Motor Neuron 1 Protein; 11128-99-7/Angiotensin II; EC Oxidase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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