Failing heart—basic scienceEndogenous endothelium-derived nitric oxide inhibits myocardial caspase activity: implications for treatment of end-stage heart failure☆
Section snippets
Materials and methods
Transgenic 9-month-old female eNOS-deficient (−/−) mice (n = 18) and age-matched wild-type (+/+) controls (n = 8) that had been back-crossed onto the parental wild-type strain for 5 generations were selected from our breeding colony. Syrian CMP hamsters (BIOTO2 strain) aged 4 months and 9 months and age-matched normal hamsters (BIOF1B strain) were obtained from Bio Breeders Inc. (Fitchburg, MA) (n = 10–12 in each group). Mice and hamsters were anesthetized with pentobarbital sodium (65 mg/kg
Controls
We used commercially available purified recombinant caspases 3, 8, and 9 as positive controls in the absence of cell lysates to investigate the ability of NO to directly inhibit caspases: 1 mmol/liter SNAP inhibited all 3 purified caspases—caspase 3 (47%), caspase 8 (13%), and caspase 9 (25%), and 0.1 mmol/liter SNAP selectively inhibited caspase 3 (by nearly 20%) but had no effect on caspase 8 or 9 (Figure 2). This suggests a direct inhibitory effect of NO on caspase 3. Unlike SNAP, L-NAME
Discussion
Reduced endothelial NO availability in heart failure increases myocardial caspase 3 enzyme activity in association with progressive ventricular remodeling and dysfunction. Agents that release NO or increase NO synthesis, including ACE inhibitor enalaprilat inhibit caspase 3 activity independent of the pathway of caspase activation and may prevent or reverse the remodeling process through inhibition of apoptosis.
Heart failure is a major health problem, with more than 500,000 new cases diagnosed
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This work was supported by HL 50142, HL 61290, and PO-1 HL 43023 from the National Heart, Lung and Blood Institute.