Abstract 299: The Cardioprotective Mechanism of a Recombinant Atrial Natriuretic Peptide Against Catecholamine-Induced Myocardial Injury in Acute Heart Failure
Background: Catecholamine induces intracellular reactive oxygen species (ROS), enhances abnormal Ca2+ handling and leads to apoptosis in failing cardiomyocytes. We clarified the mechanism by which an exogenous atrial natriuretic peptide (ANP) exerts cardioprotective effect in patients with acute heart failure (HF).
Methods and Results: Blood sampling from both coronary sinus and aorta showed that cardiac tissue produced 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, in patients with HF(n=30), but not in control subjects (n=10). Urinary (U) 8-OHdG (ng/mg creatinine) also increased in only patients with HF(Control;8.0±2.0 vs HF; 14.8±2.5, p<0.05). As protocol 1, we examined whether an infusion of ANP (0.025 µg/kg/min) decreased levels of U-8-OHdG during the treatment of HF (n=15, for 3 days), as compared with that of nitroglycerin (NTG) (n=15, for 3 days). Either treatment with ANP or NTG similarly improved hemodynamic parameters and BNP. In ANP-treated group, however, U 8-OHdG significantly decreased as compared with in NTG-treated group (ANP: 9.8±3.5; NTG: 14.5±4.2, p<0.05). As Protocol 2, we investigated the effect of ANP on 1) intracellular ROS production by DCFH-DA, 2) local Ca2+ release event by confocal microscopy using Fluo 4-AM, 3) myocyte apoptosis (TUNNEL staining) and survival rate after 48h in failing myocytes isolated from LV in canine tachycardia-induced HF(n=6, EF 20 ± 5%). In failing myocytes, isoproterenol (ISO) markedly increased intracellular ROS, concurrently with an increase in the frequency of Ca2+ sparks (SpF:s-1•100µm-1:HF: 8.0 ± 2.0 , Normal: 1.6 ± 0.5, p<0.01) . Interestingly, in failing myocytes, ANP(1x10-8 mol/L) significantly suppressed the ISO-induced ROS production, SpF, and myocyte apoptosis respectively. Eventually, the survival rate (%)in failing myocytes was significantly lower in the presence of ISO than in its absence, while it was significantly improved by co-incubation of ISO plus ANP (ISO(-);59±12, ANP(+); 63±8, ISO(+);33±13, ISO plus ANP; 55±5, p<0.01).
Conclusions: ANP has a potent antioxidant action against catecholamine-induced ROS, which may correct abnormal Ca2+ release and inhibit myocyte apoptosis, eventually contribute to improvement of myocytes survival in HF.
- Acute heart failure
- Natriuretic peptides, atrial
- Oxidative stress
- Excitation-contraction coupling (ECC)
- © 2012 by American Heart Association, Inc.