Manganese superoxide dismutase polymorphism affects the oxidized low-density lipoprotein-induced apoptosis of macrophages and coronary artery disease

Aims Oxidative damage promotes atherosclerosis. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme localized in mitochondria. We investigated the associations of the MnSOD polymorphism (valine-to-alanine in the mitochondrial-targeting domain) with its activity in leukocytes, with macrophage apoptosis by oxidized low-density lipoprotein (oxLDL), and with coronary artery disease (CAD). Methods and results Blood samples were taken from 50 healthy subjects. The mitochondrial MnSOD activities in leukocytes were 542.4 +/- 71.6 U/mg protein (alanine/alanine, n = 2), 302.0 +/- 94.9 U/mg protein (alanine/valine, n = 12), and 134.0 +/- 67.1 U/mg protein (valine/valine, n = 36; P < 0.0001 for non-valine/valine vs. valine/valine). Macrophages were treated with oxLDL. After incubation, the percentages of apoptotic macrophages were 48.6 +/- 3.6% (alanine/alanine), 78.6 +/- 9.8% (alanine/valine), and 87.5 +/- 7.0% (valine/valine) (P < 0.0001, non-valine/valine vs. valine/valine). The association of the MnSOD polymorphism with CAD was investigated using blood samples collected from 498 CAD patients and 627 healthy subjects; the alanine allele was found to reduce the risk of CAD and acute myocardial infarction (AMI). Conclusion Our data indicate that the alanine variant of signal peptide increases the mitochondrial MnSOD activity, protects macrophages against the oxLDL-induced apoptosis, and reduces the risk of CAD and AMI.