Article (Scientific journals)
Conditional neuronal nitric oxide synthase overexpression impairs myocardial contractility.
Burkard, Natalie; Rokita, Adam G.; Kaufmann, Susann G. et al.
2007In Circulation Research, 100 (3), p. 32-44
Peer Reviewed verified by ORBi
 

Files


Full Text
Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility.pdf
Publisher postprint (1.56 MB)
Request a copy

All documents in ORBilu are protected by a user license.

Send to



Details



Keywords :
Nitric Oxide Synthase Type I/antagonists & inhibitors/biosynthesis/genetics/physiology; Ornithine/analogs & derivatives/pharmacology; Protein Interaction Mapping; Recombinant Fusion Proteins/antagonists & inhibitors/biosynthesis/physiology; Sarcoplasmic Reticulum Calcium-Transporting ATPases/physiology; Stroke Volume; Ventricular Dysfunction, Left/enzymology/physiopathology/ultrasonography
Abstract :
[en] The role of the neuronal NO synthase (nNOS or NOS1) enzyme in the control of cardiac function still remains unclear. Results from nNOS(-/-) mice or from pharmacological inhibition of nNOS are contradictory and do not pay tribute to the fact that probably spatial confinement of the nNOS enzyme is of major importance. We hypothesize that the close proximity of nNOS and certain effector molecules like L-type Ca(2+)-channels has an impact on myocardial contractility. To test this, we generated a new transgenic mouse model allowing conditional, myocardial specific nNOS overexpression. Western blot analysis of transgenic nNOS overexpression showed a 6-fold increase in nNOS protein expression compared with noninduced littermates (n=12; P<0.01). Measuring of total NOS activity by conversion of [(3)H]-l-arginine to [(3)H]-l-citrulline showed a 30% increase in nNOS overexpressing mice (n=18; P<0.05). After a 2 week induction, nNOS overexpression mice showed reduced myocardial contractility. In vivo examinations of the nNOS overexpressing mice revealed a 17+/-3% decrease of +dp/dt(max) compared with noninduced mice (P<0.05). Likewise, ejection fraction was reduced significantly (42% versus 65%; n=15; P<0.05). Interestingly, coimmunoprecipitation experiments indicated interaction of nNOS with SR Ca(2+)ATPase and additionally with L-type Ca(2+)- channels in nNOS overexpressing animals. Accordingly, in adult isolated cardiac myocytes, I(Ca,L) density was significantly decreased in the nNOS overexpressing cells. Intracellular Ca(2+)-transients and fractional shortening in cardiomyocytes were also clearly impaired in nNOS overexpressing mice versus noninduced littermates. In conclusion, conditional myocardial specific overexpression of nNOS in a transgenic animal model reduced myocardial contractility. We suggest that nNOS might suppress the function of L-type Ca(2+)-channels and in turn reduces Ca(2+)-transients which accounts for the negative inotropic effect.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Burkard, Natalie
Rokita, Adam G.
Kaufmann, Susann G.
Hallhuber, Matthias
Wu, Rongxue
Hu, Kai
Hofmann, Ulrich
Bonz, Andreas
Frantz, Stefan
Cartwright, Elizabeth J.
Neyses, Ludwig ;  University of Luxembourg > Research Office
Maier, Lars S.
Maier, Sebastian K. G.
Renne, Thomas
Schuh, Kai
Ritter, Oliver
More authors (6 more) Less
Language :
English
Title :
Conditional neuronal nitric oxide synthase overexpression impairs myocardial contractility.
Publication date :
2007
Journal title :
Circulation Research
ISSN :
1524-4571
Publisher :
Lippincott Williams & Wilkins, United States - Maryland
Volume :
100
Issue :
3
Pages :
e32-44
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 16 October 2014

Statistics


Number of views
55 (1 by Unilu)
Number of downloads
0 (0 by Unilu)

Scopus citations®
 
86
Scopus citations®
without self-citations
77
WoS citations
 
82

Bibliography


Similar publications



Contact ORBilu