Document Detail


Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction.
MedLine Citation:
PMID:  11786524     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Nitric oxide (NO), a potent regulator of myocardial contractility, has been implicated in the development of heart failure; however, no study exists describing the relation between expression of inducible nitric oxide synthase (iNOS), formation of NO in vivo, and cardiac contractility. We have therefore generated transgenic (TG) mice overexpressing iNOS under the cardiospecific alpha-myosin heavy chain (alpha-MHC) promoter. In vitro, iNOS activity in hearts of two transgenic lines was 260- to 400-fold above controls (wild type [WT]), but TG mice were viable and appeared normal. Ventricular mass/body weight ratio did not differ; heart rate and cardiac output as well as mean arterial blood pressure were decreased by 10%. NO(x) levels of hearts and blood of TG mice were 2.5- and 2-fold above WT controls, respectively. In the isolated heart, release of the NO oxidation products nitrate and nitrite, an index of in vivo NOS activity, was 40-fold over WT. However, cardiac hemodynamics and levels of ATP and phosphocreatine were unaltered. The high iNOS activity was associated with reduced cardiac L-arginine in TG hearts to only 15% of the WT, indicating limited substrate availability, whereas L-citrulline was 20-fold elevated. Our findings demonstrate that the heart can tolerate high levels of iNOS activity without detrimental functional consequences. The concept that iNOS-derived NO is the triggering factor in the pathomechanism leading to heart failure therefore needs to be reevaluated.
Authors:
Jacqueline Heger; Axel Gödecke; Ulrich Flögel; Marc W Merx; Andrei Molojavyi; W Nikolaus Kühn-Velten; Jürgen Schrader
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation research     Volume:  90     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2002 Jan 
Date Detail:
Created Date:  2002-01-11     Completed Date:  2002-04-23     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  93-9     Citation Subset:  IM    
Affiliation:
Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine Universität Düsseldorf, Germany.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Transport Systems / genetics,  metabolism
Animals
Arginine / metabolism
Argininosuccinate Synthase / genetics,  metabolism
Citrulline / metabolism
Echocardiography
Female
Gene Expression
Gene Expression Regulation, Enzymologic
Heart Failure / enzymology,  physiopathology*
Hemodynamics
Immunohistochemistry
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Transgenic
Myocardium / chemistry,  enzymology*
Nitric Oxide Synthase / genetics,  metabolism*
Nitric Oxide Synthase Type II
Reverse Transcriptase Polymerase Chain Reaction
Substrate Specificity
Chemical
Reg. No./Substance:
0/Amino Acid Transport Systems; 372-75-8/Citrulline; 74-79-3/Arginine; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nos2 protein, mouse; EC 6.3.4.5/Argininosuccinate Synthase
Comments/Corrections
Comment In:
Circ Res. 2003 Oct 3;93(7):e74   [PMID:  14525922 ]

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


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