Cardiomyocyte overexpression of neuronal nitric oxide synthase delays transition toward heart failure in response to pressure overload by preserving calcium cycling.
BACKGROUND
Defects in cardiomyocyte Ca(2+) cycling are a signature feature of heart failure (HF) that occurs in response to sustained hemodynamic overload, and they largely account for contractile dysfunction. Neuronal nitric oxide synthase (NOS1) influences myocyte excitation-contraction coupling through modulation of Ca(2+) cycling, but the potential relevance of this in HF is unknown.


RESULTS
We generated a transgenic mouse with conditional, cardiomyocyte-specific NOS1 overexpression (double-transgenic [DT]) and studied cardiac remodeling, myocardial Ca(2+) handling, and contractility in DT and control mice subjected to transverse aortic constriction (TAC). After TAC, control mice developed eccentric hypertrophy with evolution toward HF as revealed by a significantly reduced fractional shortening. In contrast, DT mice developed a greater increase in wall thickness (P<0.0001 versus control+TAC) and less left ventricular dilatation than control+TAC mice (P<0.0001 for both end-systolic and end-diastolic dimensions). Thus, DT mice displayed concentric hypertrophy with fully preserved fractional shortening (43.7+/-0.6% versus 30.3+/-2.6% in control+TAC mice, P<0.05). Isolated cardiomyocytes from DT+TAC mice had greater shortening, intracellular Ca(2+) transients, and sarcoplasmic reticulum Ca(2+) load (P<0.05 versus control+TAC for all parameters). These effects could be explained, at least in part, through modulation of phospholamban phosphorylation status.


CONCLUSIONS
Cardiomyocyte NOS1 may be a useful target against cardiac deterioration during chronic pressure-overload-induced HF through modulation of calcium cycling.
Institut National de Santé et de Recherché Médicale (INSERM), Unit 689, Centre de Recherché Cardiovasculaire Lariboisière, Paris, France.
Xavier
X
Loyer
Ana Maria
AM
Gómez
Paul
P
Milliez
Maria
M
Fernandez-Velasco
Peter
P
Vangheluwe
Laurent
L
Vinet
Dominique
D
Charue
Emilie
E
Vaudin
Wei
W
Zhang
Yannis
Y
Sainte-Marie
Estelle
E
Robidel
Isabelle
I
Marty
Bernd
B
Mayer
Frédéric
F
Jaisser
Jean-Jacques
JJ
Mercadier
Sylvain
S
Richard
Ajay M
AM
Shah
Jean-Pierre
JP
Bénitah
Jane-Lise
JL
Samuel
Christophe
C
Heymes
D000818:Animals; D001011:Aorta / Q000503:physiopathology; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism*; D002469:Cell Separation; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D016277:Ventricular Function, Left
C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I; D002118:Calcium