Abstract 351: Role of Ketoaldehyde Protein Adducts in Ischemic Cardiomyopathy
Background: Oxidative damage is an important component of ischemic heart injury. Isomeric ketoaldehydes, isoketals (IsoKs), are produced by the isoprostane pathway of lipid peroxidation. IsoKs, which are among the most reactive products of lipid oxidation, form irreversible lactam adducts with lysine residues and cross-link proteins. We have identified a specific IsoK scavenger, salicylamine (SA), which prevents IsoKs from adducting to proteins in vitro. Here, we tested whether IsoK adducts are increased in ischemic cardiomyopathy and whether SA is cardioprotective.
Methods: IsoK-lysyl adducts were measured by mass spectrometry in human hearts with ischemic cardiomyopathy and in mouse hearts after MI from coronary ligation. The effect of SA was tested in the mouse MI model.
Results: IsoK adduct levels (ng/g tissue) were significantly increased in human hearts with ischemic cardiomyopathy compared with normal donor hearts (2.3±0.4 vs 0.7±0.1, p<0.05) and also in mouse hearts 7 days after MI. In vitro, IsoKs (0.5–5μM) dose dependently enhanced binding of [3H]ryanodine to cardiac SR preparations (RyR2). In mice, pre-treatment with SA for 3 days prior to coronary ligation significantly reduced overall mortality (Fig.⇓), improved cardiac contractility (fractional shortening: SA 36% vs placebo, 27%, p<0.01) and reduced infarct size (SA 18% vs placebo 36%, p<0.05) measured 7 days post MI.
Conclusion: IsoK adducts are increased in ischemic cardiomyopathy and a specific scavenger of IsoKs exerts remarkable cardioprotective effects in a mouse model of MI. IsoKs potently activate RyR2 channels, which may explain in part the cardioprotective action of IsoK scavengers.
This research has received full or partial funding support from the American Heart Association, AHA Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).