Up-regulation of cardiac nitric oxide synthase 1-derived nitric oxide after myocardial infarction in senescent rats.
Nitric oxide (NO) has been implicated in the development of heart failure, although the source, significance, and functional role of the different NO synthase (NOS) isoforms in this pathology are controversial. The presence of a neuronal-type NOS isoform (NOS1) in the cardiac sarcoplasmic reticulum has been recently discovered, leading to the hypothesis that NOS1-derived NO may notably alter myocardial inotropy. However, the regulation and role(s) of NOS1 in cardiac diseases remain to be determined. Using an experimental model of myocardial infarction (MI) in senescent rats, we demonstrated a significant increase in cardiac NOS1 expression and activity in MI, coupled with the translocation of this enzyme to the sarcolemma through interactions with caveolin-3. The enhanced NOS1 activity counteracts the decrease in cardiac NOS3 expression and activity observed in heart failure. We demonstrated an increased interaction between NOS1 and its regulatory protein HSP90 in post-MI hearts, a potential mechanism for the higher NOS1 activity in this setting. Finally, preferential in vivo inhibition of NOS1 activity enhanced basal post-MI left ventricular dysfunction in senescent rats. These results provide the first evidence that increased NOS1-derived NO production may play a significant role in the autocrine regulation of myocardial contractility after MI in aging rats.
Damy
Thibaud
T
INSERM 572, Hôpital Lariboisière, IFR J. Marrey Paris-7, Université D. Diderot, Paris, France.
Ratajczak
Philippe
P
Robidel
Estelle
E
Bendall
Jennifer K
JK
Oliviéro
Patricia
P
Boczkowski
Jorge
J
Ebrahimian
Talin
T
Marotte
Françoise
F
Samuel
Jane-Lise
JL
Heymes
Christophe
C
D000375:Aging; D000818:Animals; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000201:enzymology* / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D021381:Protein Transport; D051381:Rats; D012508:Sarcolemma / Q000201:enzymology; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000209:etiology
D018841:HSP90 Heat-Shock Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat