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(Circulation. 2004;110:3329-3334.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Dynamin-2 Regulates Oxidized Low-Density Lipoprotein–Induced Apoptosis of Vascular Smooth Muscle Cell

Yuji Kashiwakura, MD, PhD; Masami Watanabe, MD, PhD; Norihiro Kusumi, MD; Katsuhiko Sumiyoshi, PhD; Yasutomo Nasu, MD, PhD; Hiroshi Yamada, PhD; Tatsuya Sawamura, MD, PhD; Hiromi Kumon, MD, PhD; Kohji Takei, PhD; Hiroyuki Daida, MD, PhD

From the Department of Cardiology, Juntendo University School of Medicine, Tokyo (Y.K., K.S., H.D.); Departments of Urology (M.W., N.K., Y.N., H.K.) and Neuroscience (H.Y., K.T.), Okayama University Graduate School of Medicine and Dentistry, Okayama; and National Cardiovascular Center Research Institute, Osaka (T.S.), Japan.

Correspondence to Yuji Kashiwakura, MD, PhD, Department of Cardiology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail yu-kashi{at}med.juntendo.ac.jp

Received March 23, 2004; de novo received May 15, 2004; revision received June 30, 2004; accepted July 6, 2004.

Background— On exposure to oxidized low-density lipoprotein (oxLDL), vascular cells generally undergo apoptosis, which is one of the major pathogenic factors of atherosclerosis. In this study, we examined the role of dynamin (a crucial GTPase protein in endocytosis) in oxLDL-induced apoptosis of vascular smooth muscle cells (VSMC).

Methods and Results— After oxLDL stimulation, dynamin-2 colocalized with LOX-1 around the cell surface, as well as oxLDL in the cytoplasm, suggesting that dynamin-2 was involved in scavenger receptor–mediated oxLDL endocytosis. Downregulation of dynamin-2 induced by dynamin-2 dominant negative plasmid (K44A) resulted in a decrease of oxLDL uptake and thereby in a reduction of apoptosis. These data demonstrated that dynamin-2 was involved in oxLDL-induced apoptosis via the oxLDL endocytotic pathway. On the other hand, dynamin-2 wild-type plasmid transfection promoted oxLDL-induced apoptosis without increasing oxLDL uptake. Interestingly, the p53 inhibitor pifithrin- (PFT) significantly reduced apoptosis promoted by wild-type dynamin-2 (78% reduction compared with the PFT[–] condition). These results indicated that dynamin-2 enhanced oxLDL-induced apoptosis of VSMC by participating in the p53 pathway, probably as a signal transducer. Moreover, we demonstrated that, in advanced plaques of apolipoprotein E^–/– mice, dynamin-2 expression was often enhanced in apoptotic VSMC, suggesting that dynamin-2 might participate in apoptosis of VSMC even in vivo.

Conclusions— Our data demonstrated that dynamin-2 at least partially regulated oxLDL-induced apoptosis of VSMC by participating in 2 independent pathways: the oxLDL endocytotic pathway and the p53 pathway. These findings suggest that dynamin-2 may serve as a new research or therapeutic target in vascular disease.

Key Words: apoptosis • atherosclerosis • lipoproteins • cells, muscle, smooth

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