Abstract
Disruption of leptin signaling in the heart may contribute to obesity-related cardiac disease, as leptin deficient (
ob/ob) mice display cardiac hypertrophy, increased cardiac apoptosis and reduced survival. Since leptin maintains a tonic level of neuronal nitric oxide synthase (NOS1) expression in the brain, we hypothesized that leptin deficiency would decrease NOS1 cardiac expression, in turn activating xanthine oxidoreductase (XOR) and creating nitroso-redox imbalance. We studied 2- to 6-month-old
ob/ob (
n
=
26) and C57Bl/6 controls (
n
=
27). Cardiac NOS1 protein abundance (
P
<
0.01) and mRNA expression (
P
=
0.03) were reduced in
ob/ob (
n
=
10 and 6, respectively), while NOS3 protein abundance and mRNA expression were unaltered. Importantly, cardiac NOS1 protein abundance was restored towards normal in
ob/ob mice after leptin treatment (
n
=
3;
P
<
0.05 vs leptin untreated
ob/ob mice). NO metabolite (nitrite and nitrate) production within the myocardium was also reduced in
ob/ob mice (
n
=
5;
P
=
0.02). Furthermore, oxidative stress was increased in
ob/ob mice as GSH/GSSG ratio was decreased (
n
=
4;
P
=
0.02). Whereas XOR activity measured by Amplex Red fluorescence was increased (
n
=
8;
P
=
0.04), XOR and NADPH oxidase subunits protein abundance were not changed in
ob/ob mice (
n
=
6). Leptin deficiency did not disrupt NOS1 subcellular localization, as NOS1 co-localized with ryanodine receptor but not with caveolin-3. In conclusion, leptin deficiency is linked to decreased cardiac expression of NOS1 and NO production, with a concomitant increase in XOR activity and oxidative stress, resulting in nitroso-redox imbalance. These data offer novel insights into potential mechanisms of myocardial dysfunction in obesity.
