Two Novel Approaches Providing Cardiac Protection Against Oxidative Stress

Coronary artery disease is the highest contributor to morbidity and premature death in the developed world (Nabel, 2003; Fuster et al., 1992; Melo et al., 2004). Cardiac function is compromised in patients that survive an initial ischemic event and this progressive myocardial impairment leads to heart failure (Liu et al., 2007; Sugamura and Keaney, 2011; Jessup and Brozena, 2003). High levels of reactive oxygen species (ROS) contribute to the process of disease progression in both myocardial ischemia and in models of heart failure. ROS play a role in short term responses (stunning and arrhythmias) as well as long term responses (infarction) to ischemia with reperfusion. The primary source of ROS in myocardial ischemia is from mitochondria of cardiac cells with additional ROS arising from neutrophils that infiltrate ischemic regions (Sugamura and Keaney, 2011). There have been promising preclinical studies employing some antioxidant enzymes but there are no currently accepted clinical applications of these enzymes for myocardial ischemia (Downey, 1990; Zweier et al., 1987, Otani et al., 1986; Papaharalambus and Griendling, 2007; Vivekananthan et al., 2003). It is likely that the responses in the ischemic heart are more complicated than was initially realized and other antioxidant based strategies have to be developed. Our work has focused on two protective agents that act to prevent the detrimental effects of oxidative stress in the ischemic heart. The first cardio-protectant is methionine methionine sulfoxide reductase A (MsrA), a member of the Msr family of enzymes. The other major enzyme in the Msr family is MsrB and these two enzymes differ in their substrate stereo-specificity. The Msr family of enzymes can protect cells in two ways: 1) by repairing oxidative damage to critical methionine (Met) residues in proteins which have been oxidized to methionine sulfoxide (met(o)), and 2) by functioning as part of an ROS scavenger system in which Met residues in proteins function as catalytic antioxidants. MsrA has been studied in most detail and shown to protect bacterial and animal cells against oxidative damage (for review see Weissbach et al., 2005). The studies with MsrA led to investigations with the drug sulindac, a known non-steroidal anti-