Published Online
on September 26, 2005

A more recent version of this article appeared on October 4, 2005

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Submitted on May 21, 2004
Revised on May 10, 2005
Accepted on July 15, 2005

Possible Role of Brain-Derived Neurotrophic Factor in the Pathogenesis of Coronary Artery Disease

Junya Ejiri MD, PhD, Nobutaka Inoue MD, PhD^*, Seiichi Kobayashi MD, PhD, Rio Shiraki MD, Kazunori Otsui MD, Tomoyuki Honjo MD, Motonori Takahashi MD, Yoshitaka Ohashi MD, PhD, Shinobu Ichikawa MD, PhD, Mitsuyasu Terashima MD, Takao Mori MD, PhD, Kojiro Awano MD, PhD, Toshiro Shinke MD, PhD, Junya Shite MD, PhD, Ken-ichi Hirata MD, PhD, Hiroshi Yokozaki MD, PhD, Seinosuke Kawashima MD, PhD, and Mitsuhiro Yokoyama MD, PhD

From the Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine (J.E., N.I., S.K., R.S., K.O., T.H., M.T., T.S., J.S., K.H., S.K., M.Y.), and Division of Surgical Pathology, Department of Biological Informatics, Kobe University Graduate School of Medicine (H.Y.), and Division of Cardiology, Miki City Hospital (Y.O., S.I., M.T., T.M., K.A.), Kobe, Japan.

^* To whom correspondence should be addressed. E-mail: nobutaka{at}med.kobe-u.ac.jp.

Background--The neurotrophin (NT) family, including nerve growth factor NT-3 and brain-derived neurotrophic factor (BDNF), has a critical role in the survival, growth, maintenance, and death of central and peripheral neurons. NTs and their receptors are expressed in atherosclerotic lesions; however, their significance in cardiovascular disease remains unclear.

Methods and Results--To clarify the role of NTs in the pathogenesis of coronary artery disease, NT plasma levels in the aorta, coronary sinus, and peripheral veins of patients with unstable angina (n=38), stable effort angina (n=45), and non-coronary artery disease (n=24) were examined. In addition, regional expression of BDNF in coronary arteries was examined in autopsy cases and patients with angina pectoris by directional coronary atherectomy. The difference in BDNF levels, but not NT-3, between the coronary sinus and aorta was significantly greater in the unstable angina group compared with the stable effort angina and non-coronary artery disease groups. Immunohistochemical investigations demonstrated BDNF expression in the atheromatous intima and adventitia in atherosclerotic coronary arteries. BDNF expression was enhanced in macrophages and smooth muscle cells in atherosclerotic coronary arteries. Stimulation with recombinant BDNF significantly enhanced NAD(P)H oxidase activity and the generation of reactive oxygen species in cultured human coronary artery smooth muscle cells.

Conclusions--BDNF has an important role in atherogenesis and plaque instability via the activation of NAD(P)H oxidase.

Key words: circulation • coronary disease • free radicals • nervous system • stress

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