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CARDIOVASCULAR
Faculty of Pharmacy, University "Magna Graecia", Catanzaro, Italy (C.M., I.S., W.A., E.P., R.N., N.C., D.R., V.M.); Department of Cardiology, University of Rome "Tor Vergata", Rome, Italy (F.C., F.R.); Metaphore Pharmaceutical Inc., St. Louis, Missouri (D.S.); and Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, Arkansas (J.L.M.)
Received March 10, 2004; accepted June 25, 2004.
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Abstract |
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; Indolfi et al., 1995). Indeed, there is evidence that proliferation of SMCs is crucially involved in restenosis after procedures such as angioplasty (Holmes et al., 1984; Leimgruber et al., 1986; Guiteras et al., 1987; McBride et al., 1988; Indolfi et al., 1998) and arterial stenting (Roubin et al., 1992; Hoffmann et al., 1996).
Many factors have been implicated in the proliferation of SMCs subsequent to vascular injury, including the disruption of the endothelial cell layer (Harker et al., 1974; Asahara et al., 1995), the release of growth factors via activation of circulating leukocytes and macrophages (Serrano et al., 1997; Ross, 1999; Kastrati et al., 2000; Danenberg et al., 2002), and the overproduction of reactive oxygen species (ROS), which activate redox-sensitive signaling pathways (for review, see Griendling et al., 2000). All these steps lead to the remodeling of vascular architecture via induction of both cell proliferation and apoptosis (Nishio and Watanabe, 1997; Brown et al., 1999). However, the molecular and cellular mechanisms underlying these processes still remain to be elucidated.
ROS such as superoxide (
), hydrogen peroxide (H2O2), and hydroxyl radicals (OH·) can directly cause cell damage, induce the expression of proinflammatory genes, enhance the catabolism of nitric oxide via the formation of peroxynitrite (ONOO–), and accelerate the oxidative modification of low-density lipoprotein (LDL) (Griendling et al., 2000). In particular, evidence exists that ox-LDL induces endothelial expression of adhesion molecules, monocyte chemotactic protein-1, E and P-selectin, vascular cell adhesion molecule, intercellular adhesion molecule, and SMC growth factors, and impairs endothelium-dependent vasorelaxation (Cushing et al., 1990; Li and Mehta, 2000). These events occur via the activation of LOX-1, which is the most relevant receptor for ox-LDL in vascular endothelial cells (ECs) (Sawamura et al., 1997), macrophages, and activated SMCs (Yoshida et al., 1998; Chen et al., 2002). LOX-1 is a type II membrane protein with a C-type lectin-like structure at the C terminus. It is not constitutively expressed, but previous in vitro studies revealed that the expression of LOX-1 is highly induced by stimuli relevant to atherosclerosis, such as cytokines, mechanical forces, angiotensin (Ang) II, and ox-LDL itself, and to hemodynamic stress and oxidative stress (Kume and Kita, 2001; Mehta and Li, 2002). Furthermore, LOX-1 has been shown to be up-regulated in animal and human atheromatous lesions (Kume and Kita, 2001; Chen et al., 2002; Mehta and Li, 2002). These findings suggest a pivotal role for LOX-1 in atherogenesis, possibly by mediating ox-LDL-evoked ROS generation and endothelial dysfunction, which in turn leads to uncontrolled proliferation of vascular SMCs.
Recent studies have demonstrated that gene expression of LOX-1 is up-regulated by superoxide anions, H2O2, Ang II, and homocysteine in in vitro and the in vivo settings (Nagase et al., 2001). The enhanced expression of LOX-1 can be inhibited by antioxidants, indicating that restoring the antioxidant defenses in vascular tissues may be relevant in endothelial dysfunction associated with oxidative stress and enhanced LOX-1 expression (Nagase et al., 2001). However the clinical use of free radical scavengers such as recombinant human superoxide dismutase (SOD) and catalyze enzyme has shown limited effect, perhaps due to their short half-life and to their very low penetration in vascular tissues (Flaherty et al., 1994). Recently, a class of stable, nonpeptidyl low-molecular-weight molecules proven to possess selective catalytic rate toward superoxide comparable with the native SOD has been reported (Riley et al., 1996; Salvemini et al., 1999; Muscoli et al., 2003). These new SOD mimetics (SODm) represent a breakthrough in chemical design because they are stable in vivo, penetrate cells readily, have wide tissue distribution in rats, are excreted intact with no detectable dissociation, are recovered in urine and feces intact (Salvemini et al., 1999), and do not interact with other free radicals such as peroxynitrite (Muscoli et al., 2003). The use of the SODm has been suggested for treatment of diseases characterized by superoxide overproduction (Salvemini et al., 2002; Muscoli et al., 2003). In particular, evidence has been presented that M40401, a SODm (Fig. 1), exerts protective effect in many disease states, including ischemia/reperfusion injury and neurodegenerative disorders such as Parkinson and AIDS dementia complex (Mollace et al., 2002, 2003a,b). The present study was designated to evaluate 1) the relationship between carotid artery injury, ROS formation, expression of LOX-1 receptor, and SMC proliferation; and 2) the effect of novel selective SOD mimetic M40401 on both LOX-1 expression and neointina formation subsequent to vascular injury.
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Materials and Methods |
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Vascular Injury Induced by Balloon Angioplasty. The rats were anesthetized with intramuscular 100 mg/kg ketamine (Sigma Chimica, Milan, Italy) and 5 mg/kg xylazine (Sigma Chimica). Carotid artery was injured using a balloon embolectomy catheter, as described and validated previously (Indolfi et al., 1995). In brief, the balloon catheter (2F Fogarty; Baxter, Santa Ana, CA) was introduced through the right external carotid artery into the carotid artery, and the balloon was inflated at 1.5 atm pressure using a calibration device (Indeflator Plus 20; Advanced Cardiovascular System, Inc., Temecula, CA), and pulled three times. To keep the duration of the injury that might influence the vascular SMC proliferation constant, we maintained constant the time of balloon inflation to 18 s. In an additional group of rats (sham; n = 10), the effects of the anesthesia and the surgical procedure (without the balloon injury) were also assessed.
Drug Dosage and Administration. The SOD mimetic M40401 used in this study was synthesized as described previously (Salvemini et al., 1999) and was dissolved in buffered saline (pH 7.4). M40401 (0.5–10 mg/kg) or saline was given daily i.p. (0.3 ml) for 14 days after balloon injury. The same drug administration protocol was performed in sham animals.
Morphological Evaluation of the Carotid Artery. At the indicated time, animals were anesthetized with an intramuscular injection of 100 mg/kg ketamine and 5 mg/kg xylazine, and the carotid arteries were fixed by transcardial perfusion at 120 mm Hg with 100 ml of phosphate-buffered saline (pH 7.2), followed by 150 ml of 4% paraformaldehyde (pH 7.2). The carotid arteries were removed, and six cross sections were cut (each 6 µm in thickness) from the approximate mid-portion of the artery. Three sections were stained with hematoxylin & eosin to demarcate cell types, and the remaining three sections were stained with aldehyde fuchsin and counter-stained with Van Gieson's solution to demarcate the internal elastic lamina. The sections were photographed under low power, videodigitized, and stored in the image analysis system (Mipron; Kontron Electronics, Eching, Germany) in a 512 x 512 matrix with an eight-bit gray scale and a 12-field view. The media, neointima, and vessel wall were traced carefully, and the ratios between the neointima and media were calculated as shown previously (Indolfi et al., 1995). The intraobserver variability was minimal (Indolfi et al., 1995).
Malondialdehyde Determinations. MDA, used as a biochemical marker for lipid peroxidation, was measured by a method described previously (Salvemini et al., 2002). MDA was measured 3, 7, and 14 days after induction of balloon injury in carotid artery of either untreated or M40401-treated rats. Briefly, injured carotid artery of rat was surgically identified, removed, and then frozen in liquid nitrogen, and homogenized in potassium chloride (1.15%). Chloroform (2 ml) was then added to each homogenate and then spun for 30 min. The organic layer of the sample was removed and dried under nitrogen gas and reconstituted with 100 µl of saline. MDA generation was evaluated by the assay of thiobarbituric acid-reacting compounds. The addition of a solution of 20 µl of SDS (8.1%), 150 µl of 20% acetic acid solution (pH 3.5), 150 µl of 0.8% thiobarbituric acid, and 400 µl of distilled water produced a chromogenic product that was extracted in n-butanol and pyridine. Then, the organic layer was removed, and MDA levels read at 532 nm and expressed as nanomoles of MDA per gram of wet tissue.
Immunohistochemistry. Immunohistochemistry for LOX-1 and nitrotyrosine was carried out as described previously (Mehta and Li, 2002). After transcardial perfusion, the carotid arteries were fixed in 4% paraformaldehyde. Cryosections (8 µm in thickness) were incubated with the primary anti-mouse LOX-1 (1:2000; gift from Professor T. Sawamura, National Cardiovascular Center Research Institute, Osaka, Japan) and antinitrotyrosine antisera (1:2000; Cayman Chemicals, Ann Arbor, MI) overnight at 4°C, treated with the secondary biotinylated goat anti-mouse IgG antibody (Chemicon International, Temecula, CA) 1 h at room temperature, followed by peroxidase-conjugated avidin-biotin-complexes (Vectastain Elite ABC peroxidase kit; Vector Laboratories, Burlingame, CA). The reaction was visualized using a metal-enhanced 3,3'-diaminobenzidine tetrahydrochloride kit (Pierce Chemical, Rockford, IL). Quantitation of staining was then performed by densitometry using ImageQuant 5.2 software by Amersham Biosciences Inc. (Piscataway, NJ).
Western Blot Analysis. Carotid artery lysates from each experiment (30 µg/lane) were separated by 10% SDS-polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes. After incubation in blocking solution (4% dry nonfat milk; Sigma-Aldrich, St. Louis, MO), membranes were incubated with anti-LOX-1 (1: 10.000, gift from Professor T. Sawamura) overnight at 4°C. Membranes were rinsed and then incubated with anti-mouse IgG antibody (Amersham Biosciences Inc.) for 1 h at room temperature, and the specific complex was detected by an enhanced chemiluminescence detection system (Amersham Biosciences Inc.), and relative intensities of protein bands were analyzed by MSF-300G scanner.
Statistical Analysis. Results are shown as mean ± S.E.M. for n animals. Unless specified, statistical analysis was done using analysis of variance followed by post hoc Tukey's test. A P value 
0.05 was considered significant
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Treatment of rats with M40401 (0.5–10 mg/kg given i.p. daily after balloon injury) significantly antagonized balloon-induced neointima formation (n = 10 for each dose; Figs. 2 and 3). Indeed, both cross-sectional area of injured carotid artery and intima/media ratio (data not shown) were reduced dose dependently by daily administration of the M40401 SOD mimic. In addition, treating rats over the postinjury period with M40401 (0.5–10 mg/kg given i.p. daily after angioplasty; n = 10 for each dose) significantly reduced MDA formation, nitrotyrosine staining, and LOX-1 expression in vascular tissue (Figs. 4, 5, 6; Table 1). Treatments with M40401 (10 mg/kg given i.p. daily after angioplasty; n = 10) did not modified the serum cholesterol and triglyceride levels or the serum lipoproteins such as high-density lipoprotein, LDL, intermediate-density lipoprotein, and very low-density lipoprotein (data not shown). All these effects occurred by day 3, indicating that oxidative stress and LOX-1 expression are early events in the biochemical changes that can be found in vascular tissue after induction of injury and that restoring antioxidant status by treating rats with M40401 antagonized both free radical formation and LOX-1 expression, and finally, neointima formation.
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Discussion |
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This in vivo study indicates that superoxide anion generation is a crucial step in activating proliferation of subintimal SMCs, which follows vascular injury, and that LOX-1 seems to be involved in this process, which leads to the reactive neointima formation.
It is known that intracellular and extracellular production of ROS and the consequent activation of specific signaling pathways and induction of redox-sensitive genes coordinate several integrated physiological responses in vascular tissues, including growth of SMCs, induction of an inflammatory response, and impairment of endothelium-dependent relaxation (Griendling et al., 2000). In particular, production of superoxide is up-regulated by hormone-sensitive enzymes such as the vascular NAD(P)H oxidases, and its metabolism is kept under tight control by the endogenous antioxidant system such as SOD, catalase, and glutathione peroxidase. ROS serve as second messengers to activate multiple intracellular proteins and enzymes, including the epidermal growth factor receptor, c-Src, p38 mitogen-activated protein kinase, Ras, and Akt/protein kinase B (Griendling et al., 2000). Activation of these signaling cascades and redox-sensitive transcription factors leads to induction of many genes with important functional roles in the pathophysiology of vascular cells (Griendling et al., 2000). Thus, ROS participate in vascular SMC growth and migration, modulation of EC function, expression of a proinflammatory phenotype, and modification of the extracellular matrix. All these events play important roles in vascular diseases, such as hypertension and atherosclerosis, suggesting that ROS and the associated signaling pathways may represent important therapeutic targets.
Our data indicate that LOX-1 may be a crucial link between ROS generation and activation of redox-sensitive genes involved in SMC proliferation. Previous in vitro studies have indicated that LOX-1 expression is up-regulated by a host of stimuli, including inflammatory cytokines, mechanical forces, and ox-LDL (Kume et al., 1998; Aoyama et al., 1999; Kunsch and Medford, 1999). All these result in production of ROS, which have been shown to up-regulate LOX-1 in the reperfused tissues (Li et al., 2003). In addition, evidence exists that ROS can activate redox-sensitive transcription factors such as NF-
B and activator protein-1 (Kunsch and Medford, 1999) and that the ROS-related activation of NF-B and activator protein-1 leads to activation of the promoter region of the LOX-1 gene (Cominacini et al., 2000). Finally, it has recently been reported that ROS are generated upon stimulation of LOX-1 by ox-LDL, which subsequently activate the transcription factor NF-B, which in turn up-regulated Ang II type 1 receptor with subsequent overexpression of LOX-1 receptor in a positive feedback manner (Li et al., 2000). Thus, it can be suggested that the resultant ROS would further up-regulate LOX-1 expression, leading to the formation of a feedback loop (Fig. 7).
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This concept is in accordance with our data. Indeed, both generation of ROS, as shown by the nitrotyrosine staining, the footprint of the highly reactive peroxynitrite, in vascular tissues and LOX-1 expression occurred earlier than the neointima formation, which reached its peak at 2 weeks after balloon injury. On the other hand, M40401, which selectively inhibits superoxide formation, reduced ROS generation (as shown by the decrease in MDA formation and nitrotyrosine staining in injured vessels), LOX-1 expression, and finally, neointima formation, suggesting that oxidative stress triggers the cascade of events which generates, via inflammation of vascular wall and LOX-1 expression, the proliferation of SMCs that accompanied balloon injury.
In conclusion, our studies suggest that oxidative stress occurring in injured arteries triggers both LOX-1 expression and neointima formation, and this may be relevant in the treatment of vascular disorders in which proliferation of vascular smooth muscle cells and ox-LDL-related EC dysfunction occur.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: SMC, smooth muscle cell; ROS, reactive oxygen species; LDL, low-density lipoprotein; ox-LDL, oxidized low-density lipoprotein; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; EC, endothelial cell; ANG, angiotensin; SOD, superoxide dismutase; SODm, superoxide dismutase mimetic; MDA, malondialdehyde; NF-B, nuclear factor-B.
Address correspondence to: Prof. Vincenzo Mollace, Faculty of Pharmacy, University of Catanzaro "Magna Graecia", Complesso Nini' Barbieri, Roccelletta di Borgia, 88100, Catanzaro, Italy. E-mail: mollace{at}libero.it
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, P < 0.001 compared with sham; *, P < 0.05; **, P < 0.001 treated versus M40401-untreated rats.
