Abstract 70: Upregulation of Myeloperoxidase as a Novel Mechanism for Increased Myocardial Ischemic/Reperfusion Injury in Hypercholesterolemia
Hypercholesterolemia (HC) is the most-recognized risk factor for ischemic heart disease (IHD). Several recent epidemiologic studies have suggested that myeloperoxidase (MPO) overexpression is a novel risk factor for IHD. However, the relationship between these two risk factors remains unknown. The present study investigated whether a diet-induced HC may result in MPO overexpression and if so, to determine whether increased MPO activity may contribute to enhanced myocardial ischemia/reperfusion (MI/R) injury in HC animals. Male New Zealand rabbits were fed with a normal or a high cholesterol diet for 8 weeks and subjected to MI/R (1 and 4 hours). MPO expression and MPO activity in leukocytes, MPO activity and distribution in MI/R hearts, cardiac caspase-3 activity and myocardial infarct size were determined. Diet-induced HC had no effect on blood leukocyte count. However, HC caused a 7.2-fold increase in leukocyte MPO expression (P<0.01) and a 5.4-fold increase in leukocyte MPO activity (P<0.01). Moreover, MI/R-induced increase in cardiac MPO activity was markedly enhanced in HC rabbits when compared with the control rabbits (2.34±0.42 vs. 0.71±0.09 U/100 mg tissue, P<0.01). Surprisingly, MPO immunostaining was not only observed in perivascular and extracellular spaces in the I/R region, but also within I/R cardiomyocytes. This intracardiomyocyte MPO staining was further intensified by HC. In addition, MI/R-induced caspase-3 activation and myocardial infarct size were increased in HC rabbits (P<0.01) and there was a strong positive correlation between cardiac MPO activity and caspase-3 activity (P<0.01). To further establish a causative link between increased MPO expression/activity and exacerbated MI/R injury in HC, HC rabbits were treated with 4-aminobenzoic acid hydrazide (a specific MPO inhibitor, 10 mg/kg/day beginning 3 days before MI, oral gavage). Impressively, treatment with an MPO inhibitor almost abolished cardiac MPO activity and significantly reduced caspase-3 activation and infarct size (P<0.01). These results demonstrated that HC and MPO overexpression is causally related, and that anti-inflammatory agents may have significant therapeutic value in IHD patients with multiple complications such as HC.