Published online before print November 15, 2004, doi: 10.1161/01.CIR.0000147828.86593.85
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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
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.
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Abstract |
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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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Introduction |
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Apoptosis is a prominent feature in atherosclerotic lesions of humans and experimental animals and can affect macrophages, T lymphocytes, endothelial cells, and vascular smooth muscle cells (VSMC). Oxidized low-density lipoprotein (oxLDL) is one of the major atherogenic substances that induce apoptosis in many types of cells.1–4 The mechanism of oxLDL-induced apoptosis probably varies among cell types. In macrophages, oxLDL activates tumor suppressor p53 and manganese superoxide dismutase, which are responsible for apoptosis.5 In endothelial cells, the ceramide pathway or Fas-mediated pathway has been thought to mainly contribute to apoptosis.3,6 Recent studies on human atherosclerotic lesions and aneurysms revealed that p53 or Fas antigen could be detected in apoptotic VSMC of diseased vessels.7 However, most of the mechanisms that induce apoptosis in oxLDL-stimulated VSMC remain unknown.
Dynamin is a 100-kDa GTPase that is thought to pinch off vesicles from the plasma membrane at the fission step and is normally present in the cytosol as dimers or tetramers.8 Dynamin-1 and dynamin-3 are considered to be neuron- and testis-specific isoforms, respectively, whereas dynamin-2 is reported to be ubiquitous.9 During various types of endocytosis processes such as clathrin-coated pit endocytosis, caveolar endocytosis, and phagocytosis, dynamin likely assembles into a ringlike structure around the neck of the bud, where it functions directly or indirectly in pinching off vesicles from the plasma membrane.10
It has been demonstrated already that native LDL is internalized into the endosome via clathrin-coated pit endocytosis involving dynamin.11 However, no study has directly demonstrated the involvement of dynamin in oxLDL endocytosis even though it has been elucidated that CD36 and LOX-1 internalize into endosome via caveolar endocytosis (clathrin independent) or probably clathrin-coated pit endocytosis, respectively.12 Recently, however, evidence that dynamin-2 is involved in apoptosis has been reported gradually.13,14 However, there has been no study on the involvement of dynamin in apoptosis of vascular cells.
In the present study, we first attempted to validate the involvement of dynamin-2 in oxLDL uptake by VSMCs and then investigated the role of dynamin-2 in VSMC apoptosis.
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Methods |
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Cells and Cell Culture
Primary human coronary smooth muscle cells (CASMC, Chambrex) were cultured in the recommended culture medium (SmGM-2, Chambrex) containing 1% penicillin/streptomycin and other supplemented growth factors. VSMC of passages 3 to 7 were used in all experiments.
Immunocytochemistry
Cells grown in 8-well chamber slides for 2 days were washed with PSB 3 times and then fixed with 4% paraformaldehyde for 60 minutes at 4°C and permeabilized with 0.1% Triton X-100 (Sigma) before exposure to the primary antibody. Cells were exposed to blocking solution (Blockace, Yukijirushi) for 2 hours at 4°C and then to the first antibody for 1 hour at room temperature. The bound first antibody was detected with the use of the respective second antibody. Normal staining of dynamin-2 or double staining of dynamin-2 and LOX-1 in VSMC was performed 1 hour after oxLDL stimulation with the use of dynamin-2 (goat polyclonal, Santa Cruz) and/or LOX-1 (rabbit polyclonal, Santa Cruz) antibody. Second antibody for dynamin-2 or LOX-1 was Texas red–conjugated anti-goat antibody (Jackson Labs) or FITC-conjugated anti-rabbit antibody (Jackson Labs).
Preparation of Dil-Labeled OxLDL
We obtained oxLDL (90% to 100% oxidation) from Intracell Corp. With the use of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil) (Molecular Probes), labeling of oxLDL was done basically as previously described.15
Plasmid (WDp or K44A) and Transfection
The cells were seeded in 8-well chamber slides at a density of 1x105 cells per well, incubated for 24 hours, and then transfected with the respective plasmid (dynamin-2 wild-type cDNA/GFP fusion plasmid [WDp/GFP], dynamin-2 dominant negative/GFP fusion plasmid [K44A/GFP], or control GFP plasmid [EGFP-N1, original plasmid of WDp/GFP and K44A/GFP, Clontec])14 by lipofection (Invitrogen). Both the transfection efficiency and the levels of transgene expression of 3 types of plasmids in VSMC were almost the same (data not shown).
OxLDL Uptake of Plasmid (WDp/GFP or K44A/GFP)-Transfected Cells
After 24 hours of plasmid transfection, Dil-labeled oxLDL (5 µg/mL) was added to the culture medium of transfected cells. After incubation for 6 hours with oxLDL under serum-starved conditions, the cells were washed 5 times with PBS and then fixed with 4% paraformaldehyde in PBS for 30 minutes. Thereafter, Dil-fluorescent intensity of each of GFP-positive cells was determined by fluorescent microscope with the use of Meta imaging software version 6.1 (Universal Image Corporation). After the setting of consistent intensity threshold, the integrated intensity of each cell was measured.
TUNEL Assay to Detect OxLDL-Induced Apoptosis
After 24 hours of transfection, oxLDL (50 µg/mL) was added to the culture medium, and 12 hours after oxLDL stimulation under serum-starved conditions, terminal deoxynucleotidyl transferase–mediated dUTP biotin nick-end labeling (TUNEL) assay was performed. In brief, the oxLDL-stimulated cells were washed twice with PBS and fixed with 4% paraformaldehyde at room temperature for 30 minutes. The fixed cells were washed and permeabilized in 0.1% Triton X-100 (Sigma) in PBS for 3 minutes at room temperature. Finally, the cells were washed and stained with the use of the In Situ Cell Death Detection Kit (TMR-red, Roche). To investigate the role of p53 in dynamin-2–related apoptosis, pifithrin- (PFT) (50 nmol/L, Calbiochem), a p53 inhibitor, was treated in plasmid-transfected cells for 12 hours before and with oxLDL stimulation, followed by TUNEL assay.
Animals
Male apolipoprotein E (apoE)–/– mice (aged 10 weeks; C57bl/6 background) and control C57bl/6 mice were obtained from Jackson Labs. All animal work was approved by regulatory authority of Juntendo University and performed in compliance with Japanese government guidelines.
Double Immunostaining With TUNEL of Aortic Cross Section
We prepared aortic cross sections of both control and apoE–/– mice 10 weeks after Western diet, as previously described.16 Immunostaining was performed with the use of dynamin-2 and -smooth muscle actin17 (mouse, Biomeda) antibodies following the TUNEL procedure, as previously described.18 In brief, the sample was fixed with 4% paraformaldehyde for 60 minutes at room temperature and permeabilized with 0.1% Triton X-100 (Sigma) for 5 minutes at room temperature. For TUNEL assay, the sample was incubated with a reaction mixture containing the enzyme terminal deoxynucleotidyl transferase and biotinylated dNTP nucleotides (Treviegen) for 1 hour at 37°C and then incubated with 2 first antibodies (dynamin-2 and -smooth muscle actin) overnight at 4°C. Next, the sample was reacted with streptavidin Alexa Fluor 647 (Molecular Probes) together with both second antibodies tagged with Alexa Fluor 555 (anti-goat/rabbit, Molecular Probes) or Alexa Fluor 488 (anti-mouse/donkey, Molecular Probes). Additionally, we verified that the secondary antibodies did not recognize each other in control experiments.
Double staining (dynamin-2 and p53) was also performed with the use of p53 first antibody (rabbit, polyclonal, Chemicon) and anti-rabbit/donkey Alexa Fluor 488 secondary antibody (Molecular Probes).
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Results |
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On exposure to oxLDL, various molecules become activated and participate in oxLDL-induced apoptosis of vascular cells. In this study we investigated the role of dynamin-2 in oxLDL-induced apoptosis of VSMC, focusing especially on its participation in oxLDL endocytotic pathways and cell cycle pathways. Before all investigations, we preliminarily characterized the primary VSMC used in this study in regard to the expression pattern of 3 dynamin isotypes or several oxLDL receptors. VSMC expressed dynamin-2 but neither dynamin-1 nor dynamin-3. We could detect CD36, LOX-1, and SR-BI, but not SR-A, in VSMC and also confirmed that CD36 and LOX-1 were mainly responsible for oxLDL uptake in VSMC by competition assays using blocking antibodies of CD36 (BD Pharmingen), LOX-1 (JTX92),19 and SR-B (CLA-1, Novus Biologicals). After these preliminary experiments, we performed all other investigations.
The immunocytochemical study demonstrated that normally dynamin-2 distributed homogeneously in the cytoplasm (Figure 1A, a-1), whereas on oxLDL stimulation dynamin-2 shifted to the cell surface (a-2) and colocalized there with LOX-1 (Figure 1B, c, arrow). Moreover, dynamin-2 and LOX-1 colocalized with Dil-labeled oxLDL in the cytoplasm in addition to around the cell surface (Figure 1B, f and i, arrows), indicating that dynamin-2 and LOX-1 were incorporated into early endosomes together with oxLDL. We confirmed that dynamin-2 also colocalized with CD36 (data not shown). These data indicated that dynamin-2 was involved in scavenger receptor–mediated oxLDL endocytosis. Next, we investigated oxLDL uptake by VSMC where dynamin-2 was modulated. Twenty-four hours after transfection to VSMC with either WDp/GFP, K44A/GFP, or control GFP plasmid, Dil-labeled oxLDL uptake by VSMC was attempted. K44A/GFP transfection decreased oxLDL uptake significantly, whereas WDp transfection had no influence on oxLDL uptake (Figure 2). These results demonstrated that downregulation of dynamin-2 directly affected oxLDL uptake, although dynamin-2 overexpression alone could not enhance oxLDL endocytosis. On the basis of these findings, we concluded that dynamin-2 was one of the essential factors of oxLDL endocytosis.
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Next, we investigated oxLDL-induced apoptosis in VSMC where dynamin-2 was modulated. Twenty-four hours after transfection with the respective plasmid, oxLDL stimulation (50 µg/mL) was performed for 12 hours to induce apoptosis, followed by TUNEL assay. Apoptosis was hardly detected in the absence of oxLDL in the 3 types of GFP-positive cells (Figure 3A, slashed bars). Among the control GFP-positive cells, the frequency of apoptosis was 42% (Figure 3A, lane pEGFPN1, black bar). Apoptotic cells were recognized much less frequently among K44A/GFP-positive cells (Figure 3B; top panels show a typical nonapoptotic cell) than among control GFP-positive cells (Figure 3A, black bar, 24% versus 42%). Given the previous report that K44A, a mutant defective GTP binding, could work as dominant negative in endocytotic pathways but not in apoptotic pathways,13 the inhibition of apoptosis was probably due solely to the decrease of oxLDL uptake. Our data suggested that dynamin-2 downregulation reduced oxLDL-induced apoptosis by decreasing oxLDL uptake, which meant that dynamin-2 was involved in oxLDL apoptosis of VSMC via oxLDL endocytotic pathway. On the other hand, apoptosis could be detected more frequently among WDp/GFP-positive cells (Figure 3B; bottom panels show a typical apoptotic cell) than among control GFP-positive cells (Figure 3A, black bar, 93% versus 42%) even though there was no difference in the amount of oxLDL uptake between the 2 types of cells (Figure 2). In short, an increase of wild-type dynamin-2 did not affect oxLDL endocytosis but led to the promotion of apoptosis. These results suggested that on exposure to oxLDL, dynamin-2 also participated in some pathway related to apoptosis, besides the oxLDL endocytotic pathway.
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To identify such an interesting pathway, we examined the effect of the p53 inhibitor PFT on apoptosis of cells overexpressing dynamin-2. After treatment with PFT (50 nmol/L) for 12 hours, oxLDL was added to the culture medium, followed by TUNEL assay. The results showed that PFT significantly reduced apoptosis of WDp/GFP-transfected cells by 78%, whereas it reduced apoptosis of control GFP-positive cells by only 45% (Figure 3A, white bars). As a result of PFT treatment, the final percentage of apoptotic WDp/GFP-transfected cell was almost the same as that of apoptotic control cells (
20%). These data indicated that the p53 pathway might be mainly responsible for the apoptosis promoted by overexpressed dynamin-2. We speculated that the apoptosis observed despite treatment with PFT was mediated through pathways different from the p53 pathway.7 We also performed the same experiments using Fas ligand neutralizing antibodies or tumor necrosis factor- receptor I and II neutralizing antibodies. These results showed that both blocking antibodies could not reduce the percentage of apoptotic cells among WDp-transfected cells to that in control cells (data not shown), suggesting that dynamin-2 is not likely to be involved in either Fas/Fas ligand or in the TNF-–mediated apoptotic pathway. Our findings suggested that dynamin-2 promoted oxLDL-induced apoptosis by participating only in the p53 pathway.
We also investigated in vivo dynamin-2 expression in advanced plaque in serial cross sections of the aorta from apoE–/– mice (Figure 4c; arrows indicate advanced plaque) and control mice (Figure 4a; no intima). Immunostaining demonstrated that there was a population of cells that strongly expressed dynamin-2 (Figure 4d; arrow) in the advanced plaque but not in the media (Figure 4b). Double staining with TUNEL assay revealed that the average frequency of apoptosis in intimal cells (5 mice) was 2.8% (range, 0.6% to 5.4%). Interestingly, dynamin-2 expression was often enhanced in apoptotic VSMC (Figure 5A, 1 to 4; white arrow indicates dynamin-2–positive apoptotic VSMC). Moreover, p53 expression could be detected in several apoptotic cells overexpressing dynamin-2 (Figure 5B, arrow), implicating the participation of dynamin-2 in the p53 pathway in vivo. One sixth of p53-positive apoptotic vascular cells were dynamin-2 positive, whereas all dynamin-2–positive apoptotic cells were p53 positive. Given these quantitative results, dynamin-2 may play an additional rather than an essential role in the p53-dependent apoptotic pathway. Recently, several studies demonstrated abnormalities of endocytosis-related proteins such as dynamin in some diseases. For instance, a correlation has been reported between dynamin-related protein abnormalities and inherited optic neuropathy.20 However, no study has analyzed atherosclerosis from the viewpoint of dynamin. Our data suggest that dynamin-2 might be involved in apoptosis of intimal migratory cells, even in vivo.
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Discussion |
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The mechanism by which dynamin-2 is involved in the apoptotic pathway has been explored only minimally. Dynamin-2 has been shown to interact with several signaling molecules such as ERK kinase and grb2.21,22 We speculate that dynamin governs membrane dynamics at the cell surface to thereby activate the p53-dependent apoptotic cascade. It has been demonstrated that inhibition of Rac, a member of the Rho superfamily, elicits a p53-dependent apoptotic response.23 Interestingly, dynamin has been reported to translocate Rac from the cell surface to the perinucleus and then deactivate Rac by inversing Rac-GTP to Rac-GDP.24 Given these reports, dynamin-2 may participate in the p53-dependent pathway by modulating Rac localization and activity.
In conclusion, our data demonstrated that dynamin-2 at least partially regulated oxLDL-induced apoptosis of VSMC by participating in at least 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.
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References |
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