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European Heart Journal Advance Access originally published online on October 29, 2007
European Heart Journal 2008 29(10):1267-1274; doi:10.1093/eurheartj/ehm500
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

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

Hajime Fujimoto1, Jun-ichi Taguchi2, Yasushi Imai1, Seiji Ayabe1, Hideki Hashimoto3, Hisae Kobayashi1, Ken Ogasawara4, Tadanori Aizawa4, Minoru Yamakado5, Ryozo Nagai1 and Minoru Ohno6,*

1 Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan
2 Department of Cardiovascular Medicine, Tokai University, Tokyo, Japan
3 Department of Health Management and Policy, University of Tokyo Graduate School of Medicine, Tokyo, Japan
4 The Cardiovascular Institute, Tokyo, Japan
5 Mitsui Memorial Hospital, Tokyo, Japan
6 Cardiovascular Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo 105-8470, Japan

Received 23 January 2007; revised 25 September 2007; accepted 4 October 2007; online publish-ahead-of-print 29 October 2007.

* Corresponding author. Tel: +81 3 3588 1111, Fax: +81 3 3582 7068. Email: mino-tky{at}umin.ac.jp

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.

Key Words: Apoptosis • Macrophage • Oxygen radicals • Coronary disease • Gene expression


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