Abstract 14031: Scavengers of Hyper-Reactive Oxidized Lipid Aldehydes Prevent Abnormal Calcium Handling of Ventricular Myocytes After Myocardial Infarction
Oxidative damage is an important component of ischemic heart injury. The molecular mechanisms that contribute to dysfunctional myocyte Ca handling after myocardial infarction (MI) are incompletely understood. Oxidative stress also produces a class of hyperreactive lipid aldehydes that are generated non-enzymatically from membrane arachidonic acid (γ-ketoaldehydes, γKAs). Recently, we found that the pyridoxamine analogue, salicylamine (SA) scavenges γKAs and thereby prevents formation of γKA protein adducts in response to oxidative stress. We hypothesized that pre-treatment of SA in vivo would prevent the accumulation of γKA protein adducts, Ca handling dysfunction, and spontaneous Ca waves post MI.
Methods: Mice treated with either SA or vehicle (VEH) underwent coronary ligation. γKA protein formation was quantified by mass spectrometry, and Ca handling measured in isolated myocytes from remote (RE) and peri-infarct (MI) zone of the myocardium.
Results: γKA-protein adducts were significantly increased in the peri-infarct and did not change in the remote myocardium (Fig. A). Importantly, SA treatment prevented γKA protein adduct formation 7 days post MI (n=3 per group). Compared to myocytes isolated from the remote zone which does not contain increased adducts, peri-infarct zone myocytes had significantly depressed the Ca transients and SR Ca contents. Treatment with SA significantly improved Ca handling in peri-infarct myocytes (VEH-RE; 0.49±0.05, VEH-MI; 0.28±0.04*, SA-MI; 0.40±0.05, n=19-34, *p<0.05). Furthermore, SA treatment significantly reduced spontaneous Ca waves (% of cells, VEH-RE; 6%, VEH-MI; 20%*, SA-MI; 6%, n=61-85, *p<0.05, Fig. B).
Conclusion: γKA scavenger treatment reduces γKA-protein adducts after MI and improves Ca handling of myocytes isolated from the peri-infarct zone. The protective effect of γKA scavengers suggests that γKAs are important mediators of oxidative stress-induced RyR2 channel dysfunction in vivo.
- © 2011 by American Heart Association, Inc.