Document Detail


Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency.
MedLine Citation:
PMID:  18474859     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We recently demonstrated early metabolic alterations in the dystrophin-deficient mdx heart that precede overt cardiomyopathy and may represent an early "subclinical" signature of a defective nitric oxide (NO)/cGMP pathway. In this study, we used genetic and pharmacological approaches to test the hypothesis that enhancing cGMP, downstream of NO formation, improves the contractile function, energy metabolism, and sarcolemmal integrity of the mdx heart. We first generated mdx mice overexpressing, in a cardiomyocyte-specific manner, guanylyl cyclase (GC) (mdx/GC(+/0)). When perfused ex vivo in the working mode, 12- and 20-week-old hearts maintained their contractile performance, as opposed to the severe deterioration observed in age-matched mdx hearts, which also displayed two to three times more lactate dehydrogenase release than mdx/GC(+/0). At the metabolic level, mdx/GC(+/0) displayed a pattern of substrate selection for energy production that was similar to that of their mdx counterparts, but levels of citric acid cycle intermediates were significantly higher (36 +/- 8%), suggesting improved mitochondrial function. Finally, the ability of dystrophin-deficient hearts to resist sarcolemmal damage induced in vivo by increasing the cardiac workload acutely with isoproterenol was enhanced by the presence of the transgene and even more so by inhibiting cGMP breakdown using the phosphodiesterase inhibitor sildenafil (44.4 +/- 1.0% reduction in cardiomyocyte damage). Overall, these findings demonstrate that enhancing cGMP signaling, specifically downstream and independent of NO formation, in the dystrophin-deficient heart improves contractile performance, myocardial metabolic status, and sarcolemmal integrity and thus constitutes a potential clinical avenue for the treatment of the dystrophin-related cardiomyopathies.
Authors:
M Khairallah; R J Khairallah; M E Young; B G Allen; M A Gillis; G Danialou; C F Deschepper; B J Petrof; C Des Rosiers
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-05-12
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  105     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-05-14     Completed Date:  2008-05-28     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7028-33     Citation Subset:  IM    
Affiliation:
Montreal Heart Institute, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Atrial Natriuretic Factor / genetics,  metabolism
Cardiomyopathies / enzymology,  physiopathology,  prevention & control*
Cyclic GMP / metabolism*
Dystrophin / deficiency*
Enzyme Activation / drug effects
Gene Expression Regulation / drug effects
Guanylate Cyclase / genetics,  metabolism
Heart Rate / drug effects
Mice
Mice, Transgenic
Mitochondria / drug effects,  metabolism
Myocardial Contraction / drug effects
Myocytes, Cardiac / drug effects*,  enzymology,  metabolism*,  pathology
Organ Specificity / drug effects
Piperazines / pharmacology*
Purines / pharmacology
Sarcolemma / drug effects,  metabolism
Signal Transduction / drug effects*
Sulfones / pharmacology*
Grant Support
ID/Acronym/Agency:
HL-074259-01/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Dystrophin; 0/Piperazines; 0/Purines; 0/Sulfones; 3M7OB98Y7H/sildenafil; 7665-99-8/Cyclic GMP; 85637-73-6/Atrial Natriuretic Factor; EC 4.6.1.2/Guanylate Cyclase
Comments/Corrections

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