Visit our Expo - Redox and Inflammation signaling 2012

Session IX. Novel compounds targeting inflammatory signaling pathways Poster IX, 2
NAC prevents cardiac maladaptative responses to hypertension and promotes TNFR-2
signaling in cardiomyocytes
Nicole Defer1, Gabriele Candiani1, Jin-Bo Su2, Marie Bourraindeloup2, Luc Hittinger2,
Françoise Pecker1 and Catherine Pavoine1
1INSERM U581; Université Paris 12, Faculté de Médecine; Créteil, F-94000 France;
2INSERM U660; Université Paris 12, Faculté de Médecine; Créteil, F-94000 France;
The aim: Our previous in vivo studies showed that N-acetylcysteine (NAC) was a potential
therapeutical tool for the management of hypertension–induced heart failure. However, early
mechanisms of NAC action remained to be defined.
Results and Methods: Rats were given a four week treatment with the nitric oxide synthase
inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day in drinking water) and
high salt diet (HS, 8% NaCl). HS/L-NAME rats displayed hypertension-induced adaptative
responses, characterized by thickening of ventricular walls and eccentric hypertrophy of
cardiomyocytes, without left ventricular dysfunction. This was associated with changes in two
early biochemical markers of adaptative cardiac responses, namely decrease in beta-1adrenergic
(AR) stimulation of adenylyl cyclase (AC) and increase in the number of the type
1 TNF receptors (TNFR-1) over TNFR-2. NAC treatment (125 mg/kg/day in drinking water)
given during weeks 3 and 4 of HS/L-NAME administration, had no effect on hypertension,
but triggered a proportional hypertrophy of cardiomyocytes and prevented alterations of both
beta-1-AR/AC signaling and TNFR-1/TNFR-2 ratio. Imaging studies performed on
electrically stimulated cardiomyocytes isolated from control rats treated for 2 weeks with
NAC, showed that NAC blunted TNF- induced production of ROS and its associated negative
effect on Ca transient amplitude. Neutralizing anti-TNFR-1 antibodies mimicked these effects
of NAC in cardiomyocytes isolated from control untreated rats. Furthermore, NAC
uncovered a strong enhancing effect of TNF on Ca transients, that was associated with
phosphorylation of Erk, Akt and PKC zeta and activation of the cPLA2. These TNF effects
were impaired by anti TNFR-2 antibodies.
Conclusion: Our results highlighted NAC as a tool favouring TNFR-2 while blunting TNFR-1
signaling pathways, and counteracting early maladaptative responses to hypertension.
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