Ann Thorac Surg 2005;80:1773-1778
© 2005 The Society of Thoracic Surgeons
Original article: Cardiovascular
Effects of Resveratrol in Storage Solution on Adhesion Molecule Expression and Nitric Oxide Synthesis in Vein Grafts
Sadi Kaplan, MD
a
,
*
,
Jeffrey A. Morgan, MD
a
,
Gianluigi Bisleri, MD
a
,
Faisal H. Cheema, MD
a
,
Hasan O. Akman, PhD
b
,
Veli K. Topkara, MD
a
,
Mehmet C. Oz, MD
a
a Department of Cardiothoracic Surgery, College of Physicians and Surgeons, Columbia University, New York, New York
b Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York
Accepted for publication April 25, 2005.
* Address correspondence to Dr Kaplan, 2 Dedeefendi Altay Sokak 4/11, Kurtulus, 06600, Ankara, Turkey (Email: skaplan{at}bir.net.tr).
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Abstract
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BACKGROUND: Endothelial injury in human saphenous vein grafts may occur during harvesting and storage, which may have an adverse effect on coronary artery bypass grafting outcome. In this study, we sought to determine whether resveratrol, a natural antioxidant enriched in grape, can limit endothelial activation and reduce endothelial injury in human saphenous vein grafts.
METHODS: Human saphenous vein grafts, obtained from 8 patients and divided into two equal groups of control and study specimens, were stored in either heparinized blood (group A) or heparinized blood containing 50 µg/mL resveratrol (group B) for 1 hour at room temperature. Specimens were analyzed by Western blotting to quantify intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and inducible nitric oxide synthase-2 expression, as well as tissue cyclic guanylate monophosphate levels. Myeloperoxidase activity, a marker of neutrophil sequestration in human saphenous vein grafts, was also measured in each group.
RESULTS: Intercellular adhesion molecule-1 expression (1,674 ± 332 versus 559 ± 282; p = 0.003), vascular cell adhesion molecule-1 expression (753 ± 183 versus 472 ± 151; p = 0.025), and myeloperoxidase activity (7.00 ± 1.05 versus 1.33 ± 0.45 nm/min; p = 0.004) were significantly lower in group B. In contrast, inducible nitric oxide synthase-2 expression (548 ± 237 versus 2,234 ± 726; p = 0.004) and tissue cyclic guanylate monophosphate levels (2.02 ± 0.53 versus 5.61 ± 0.89 pmol/mL; p = 0.001) were significantly higher in group B.
CONCLUSIONS: Resveratrol reduced upregulation of leukocyte–endothelial cell adhesion molecule expression in human saphenous vein graft endothelium and decreased neutrophil adhesion to saphenous vein graft endothelium. Resveratrol also augmented inducible nitric oxide synthase-2 expression and increased cyclic guanylate monophosphate levels. These results suggest that resveratrol might improve vascular homeostasis and reduce endothelial injury during the hypoxic storage period of human saphenous vein grafts for coronary artery bypass grafting.
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Introduction
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Autologous saphenous vein is widely used as a bypass conduit in coronary artery bypass grafting, although its long-term patency is lower compared with arterial conduits [1]. When technical reasons are excluded, anatomic damage and endothelial dysfunction occurring during harvesting and perioperative storage of human saphenous vein grafts (HSVGs) has been identified as a major factor responsible for graft occlusion [1–10]. In current practice, short-term storage of free vascular grafts is routine in coronary artery bypass graft operations, and during the storage interval, hypoxia [10–12], duration of ischemia, and composition of the storage solution [2, 4, 5, 8, 9] may affect the integrity of the graft endothelium. Therefore, the intraoperative preservation of harvested HSVGs is an important issue for the protection of endothelial cell function. However, in clinical practice, preservation of HSVGs between the time of harvest and implantation has received little attention, possibly because conduits are thought by many surgeons to not be particularly sensitive to hypoxic damage.
The neutrophil–endothelial cell interaction plays an important role in endothelial injury and pathogenesis of HSVG occlusions [2, 6, 7, 13]. Leukocyte adhesion to endothelium is regulated by the presence of leukocyte–endothelial cell adhesion molecules on the surface of endothelial cells, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and circulating neutrophils (CD11b/CD18) [1, 4, 13]. Under in vivo physiologic conditions, none or only a few adhesion molecules are expressed on the intact HSVG endothelium [13, 14], although enhanced adhesion molecule expression has been observed in failed HSVGs [3]. It has been demonstrated that hypoxia, composition of storage media [2, 5], oxidative stress [10, 12], decreased endothelial nitric oxide (NO) synthesis, and lower tissue cyclic-3',5'-guanosine monophosphate (cGMP) levels [12, 15] can significantly influence adhesion molecule expression.
The endothelium produces NO from L-arginine [15,16]. Nitric oxide is respected as an important marker and integral mediator of endothelial cell functionality. It activates guanylyl cyclase and increases intracellular concentrations of cGMP in platelets and smooth muscle cells [15, 16]. Nitric oxide regulates vascular tone and plays a significant role in leukocyte–endothelium interactions [12, 15, 16]. Moreover, it is believed that endogenous NO and cGMP might contribute to suppress inflammation in vivo through the suppression of endothelial adhesion molecule expression. Unfortunately, it has been demonstrated that the harvesting process [1, 2, 4, 14, 16–18] as well as storage-related hypoxia–ischemia [1–3, 5, 8, 9] causes a decrease in endothelial NO synthesis in HSVGs.
Resveratrol (3,5,4'-trihydroxy-stilbene), a polyphenol present in wine, has been thought to be responsible for the cardiovascular benefits associated with moderate wine consumption [19]. Besides the vasodilatory effects of resveratrol [19], it exerts significant antioxidant [19], antiplatelet [20], and antiinflammatory [21] effects. Moreover, resveratrol was recently found to enhance NO production in various organs such as endothelial cells [19, 22, 23] and heart [19, 22, 24], and consequently to exert a beneficial effect on several organs in ischemia–reperfusion injury [19, 22–24]. In this study, we sought to determine whether resveratrol, when added to the preservation solution, can limit endothelial activation and reduce endothelial injury by inhibiting leukocyte–endothelial adhesion molecule expression and neutrophil adhesion to endothelial cells, as well as by increasing endothelial NO production and cGMP levels in endoscopically harvested HSVGs.
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Material and Methods
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Chemicals
Resveratrol was purchased from Sigma (resveratrol, 99% purity; Sigma Chemical Co, St. Louis, MO). Resveratrol solution was prepared fresh at desired doses in a sterile manner in 0.9% saline solution, with light protection before use.
Experimental Protocol
Segments of human saphenous veins were obtained from 8 patients undergoing elective coronary artery bypass grafting before distention or any other manipulation. Criteria for exclusion from the study were diabetes mellitus, peripheral arterial obstructive disease, varicoses, chronic inflammation states, and recent use of steroids.
A 2-cm segment of freshly isolated vein was taken from the upper portion of the long saphenous vein using endoscopic harvesting technique (Guidant Cardiac Surgery Products, Santa Clara, CA). Each specimen was measured and divided into two segments of equal length (1 cm each), representing the control and the study specimen. Two groups of tubes containing 5 mL of heparinized autologous blood were set up as described below: group A: control, heparinized blood only; group B: heparinized blood plus 5 mL of resveratrol solution at a concentration of 50 µg/mL. Both samples were then stored at room temperature for 60 minutes, which is similar to the average storage period for a harvested vein before implantation as a bypass conduit. Each specimen was rinsed briskly in normal saline solution three times (the samples were rinsed before freezing to avoid errors in the myeloperoxidase measurements owing to nonadherent leukocytes), divided into three approximately equal parts (one segment for ICAM-1 and VCAM-1 measurements, one segment for myeloperoxidase assay, and one segment for inducible nitric oxide synthase-2 [INOS-2] and cGMP analysis), snap-frozen in liquid nitrogen, and stored separately in a –80°C freezer until analysis. This study was conducted in accordance with the Columbia University Institutional Review Board approval (IRB 0988).
Assays
Western blotting
Tissue samples were homogenized for 30 seconds at 4°C with a Polytron homogenizer (Fisher Scientific, Kinematica, AG, Littau, Switzerland) with ice-cold 20 mmol/L Tris hydrogen chloride (HCl), pH 7.4, containing 100 mmol/L sodium chloride, 0.5% NP-40 (Roche, Indianapolis, IN), 2 mmol/L phenylmethylsulfonyl fluoride (PMSF), 0.5 mg/L leupeptin, and 0.7 mg/L pepstatin. Homogenates were shaken at 4°C for 0.5 hours and then centrifuged (14,000 rpm for 10 minutes at 4°C). The supernatant was collected as the source of sample protein. Samples were run in a 10% polyacrylamide gel and then transferred to a nitrocellulose membrane (Invitrogen, Carlsbad, CA). The membrane was blocked for nonspecific binding using 1% bovine serum albumin (BSA) in phosphate-buffered saline (PBS) for 16 hours at 4°C. The membrane was then incubated in 0.05% BSA and 0.05% Tween 20 in PBS containing goat anti-mouse ICAM-1 (R&D Systems Inc, Minneapolis, MN) antibody at 1:1000 dilution for 1 hour. After subsequent washes, the membrane was incubated with anti-goat IgG–peroxidase conjugate (Sigma Chemical Co, St. Louis, MO) at 1:2000 dilution in PBS, 0.5% BSA, and 0.05% Tween 20 for 45 minutes. After the subsequent washes, roentgenogram films were obtained using enhanced chemiluminescence detection (Amersham, Piscataway, NJ). The staining intensity of specific bands was quantified by densitometric scanning, using NIH image program, by computer software (Molecular Analyst, Bio-Rad Laboratories). Those calculated areas were then statistically compared. The same procedure was repeated for the detection of VCAM-1 using corresponding antibodies (R&D Systems Inc, Minneapolis, MN) and INOS-2 using a mouse-derived anti-INOS-2 antibody (Santa Cruz Biotechnology Inc, Santa Cruz, CA) and an anti-mouse IgG–peroxidase conjugate (Sigma Chemical Co) at 1:2000 dilution.
Enzyme-linked immunosorbent assay
Saphenous vein tissue homogenates in PBS were added to 5% trichloroacetic acid and kept on ice for 30 minutes. Those homogenates were spun at 4,000 rpm for 15 minutes. Supernatant was collected and washed with ether three times. After storing the homogenates at 20°C for 5 minutes, cGMP content of HSVGs was measured by a second-generation enzyme-linked immunosorbent assay kit (R&D Systems Inc).
Myeloperoxidase assay
To determine the neutrophil adhesion to HSVGs endothelium after harvesting and 1-hour storage period, HSVG tissue activity of myeloperoxidase, an enzyme occurring in neutrophils, monocytes, and macrophages, was measured using the method described previously by Mullane and colleagues [25].
Statistical Analysis
All statistics were obtained using SPSS statistical software (release 10.0; SPSS Inc, Chicago, IL). All continuous variables are expressed as mean ± standard deviation. Comparisons between groups were made by Student's t test or Mann-Whitney U test, as applicable. Probability values lower than 0.05 indicated statistically significant differences.
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Results
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Cellular Adhesion Molecule Expression
Five of the patients were male. The mean age of the patients was 66.7 ± 7.3 years. The mean value of ICAM-1 expression, quantified as the intensity of a given band on the Western blot, was 1,674 ± 332 in group A versus 559 ± 282 in group B (p = 0.003; Figs 1 and 2).
The mean intensity for scanned bands for groups A and B was 753 ± 183 versus 472 ± 151 for VCAM-1, respectively (p = 0.025).
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Fig 1. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and inducible nitric oxide synthase-2 (INOS-2) expression of human saphenous vein segments, quantified as the intensity of a given band on the Western blot, presented as mean ± standard deviation. Filled bars indicate control group and open bars indicate resveratrol-treated group vein grafts (p = 0.003 for ICAM-1; p = 0.025 for VCAM-1; and p = 0.004 for INOS-2).
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Fig 2. Representative immunoblot demonstrating intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase-2 (INOS-2) expression. Each specimen was taken from a given patient and divided into two equal parts, one being treated with heparinized blood (control group) and the other with resveratrol in heparinized blood (study group). Control lane represents a single patient, with the data from the corresponding vein segment from the same patient shown for resveratrol-treated segments.
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Inducible Nitric Oxide Synthase-2 Expression
Measured intensity of INOS-2 bands was significantly higher in resveratrol-treated HSVG segments compared with the control group (548 ± 237 for group A versus 2,234 ± 726 for group B, respectively; p = 0.004; Figs 1 and 2).
Cyclic Guanosine Monophosphate Content
Enzyme-linked immunosorbent assays were performed to quantify saphenous vein cGMP levels. Assay of homogenates demonstrated that human saphenous vein tissue total cGMP levels were higher in the resveratrol-treated group (group B) than in the control group (group A; 5.61 ± 0.89 pmol/mL versus 2.02 ± 0.53 pmol/mL, respectively; p = 0.001; Fig 3).
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Fig 3. Human saphenous vein graft tissue cyclic guanosine monophosphate (cGMP) levels, determined by enzyme-linked immunosorbent assay, presented as mean ± standard deviation. Filled bar indicates control group and open bar indicates resveratrol-treated group vein grafts.
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Myeloperoxidase Activity
Mean myeloperoxidase activity was significantly lower in the resveratrol-treated vein segments in comparison with the control group (1.33 ± 0.45 nm/min for group B versus 7.00 ± 1.05 nm/min for group A, respectively; p = 0.004; Fig 4).
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Fig 4. Effect of resveratrol preservation on human saphenous vein graft neutrophil accumulation after 1-hour waiting period. Myeloperoxidase activity (MPO; change in absorbance at 460 nm/min) was determined to quantify neutrophil deposition in the vein grafts. Filled bar indicates control group and open bar indicates resveratrol-treated group vein grafts. Data for samples are shown as group mean ± standard deviation. For each group, n = 8.
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Comment
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The endothelium, the leading target organ in ischemia–reperfusion injury, is a central regulator of vascular homeostasis and plays a major role in maintaining vascular integrity. Various studies have identified endothelial damage in HSVGs as a major cause of graft failure. Investigations have demonstrated that endothelial trauma may occur at the time of harvest, owing to surgical trauma, stretch [1, 6, 7, 14, 17, 18], ischemia, free radical generation during hypoxic ex vivo preservation, storage conditions [1–3, 5, 8, 9], and distention before anastomosis and at the time of graft insertion [14]. Current practice is primarily focused on prevention of mechanical causes of endothelial injury. In this regard, meticulous harvesting, pharmacologic dilatation, and avoidance of overdistention of an HSVG have been recognized as important steps during procurement, which may preserve graft function. Hypoxia might shift the endothelial phenotype toward to one in which anticoagulant properties are diminished, permeability and leukoadhesivity are increased, and proinflammatory features dominate the endovascular milieu during the storage of venous grafts [11]. Therefore, significant endothelial injury in HSVGs may occur during the hypoxic storage period. Consequently, the preservation of endothelial cell functions during storage of vein grafts may be vital for inhibiting early pathologic changes in HSVGs [2, 3, 5, 8, 9].
Adhesion molecules, ICAM-1, VCAM-1, and P-selectin, expressed on endothelial cells, mediate the binding of leukocytes to endothelial cells through interactions with their counterreceptors on leukocytes [13]. Circulating leukocytes adhere to the vessel wall by means of those molecules and cause a considerable amount of damage to the vascular endothelium and adjacent tissues [13, 14, 16]. Under physiologic conditions, adhesion molecule expression on segments of recently harvested saphenous vein is very low or usually almost absent [4, 13, 14]. During the storage period, HSVG endothelial cells retain their ability to synthesize leukocyte chemoattractants such as interleukin 8 [26], and adhesion receptors and storage procedures upregulate the expression of such molecules [5–9, 19]. Therefore, attenuation of adhesion molecule expression during the storage period may be potentially beneficial in preventing leukocyte adhesion to the vessel wall and suppressing neutrophil-mediated endothelial injury in HSVGs.
In a preliminary study, we examined ICAM-1, VCAM-1, and INOS-2 expression in endoscopically harvested vein grafts just after harvesting (unpublished data). In accordance with previous studies, we could not obtain any visible band staining for adhesion molecules and INOS-2 (indicating their expression) or determine a basal level for these molecules in HSVG by Western blotting method. We assumed that it might be too early for their expression to be detected by Western blotting method, as endothelial adhesion molecule expression on endothelium requires time because of gene transcription and protein synthesis [16, 27]. Therefore, in this study, we allowed for an hour of storage period before measuring adhesion molecule expression in the grafts. By comparing matched pairs of vein tissue, we demonstrated that a 60-minute period of storage in heparinized blood after harvesting results in an increased expression of the endothelial adhesion molecules, ICAM-1 and VCAM-1, in HSVG. Furthermore, there was also a high myeloperoxidase activity in the corresponding grafts, indicating an increase in neutrophil adhesion to the graft endothelium and proinflammatory reaction in the grafts. In contrast, when compared with the control grafts, resveratrol-enriched storage solution seemed to provide better endothelial cell function in HSVGs, as demonstrated by decreased expression of adhesion molecules and lower myeloperoxidase activity in the resveratrol-preserved group compared with the control group. These results demonstrate that hypoxic storage may cause significant endothelial injury in all HSVG. The storage period per se may be associated with increased expression of endothelial adhesion molecules in venous grafts in both groups. Treatment with resveratrol, however, seems to minimize endothelial injury and suppress adhesion molecule upregulation. This was confirmed with our findings of decreased adhesion molecule expression and myeloperoxidase activity in the resveratrol-preserved group.
Nitric oxide is derived enzymatically from the oxidation of L-arginine by nitric oxide synthase (NOS), which exits in three isoform; neuronal NOS, endothelial NOS, and inducible NOS [27]. Endothelial NOS is found in venous, arterial, and capillary endothelial cells, as well as myocytes and platelets. Endothelial NOS transcription is increased by hypoxia [27]. Inducible NOS is found in various tissues, such as vein grafts, and its expression is induced by immunoactivation of neutrophils, macrophages, and monocytes [27, 28]. Their induction generally reflects a pathophysiologic cellular response to immunoactivation and elicits vasoplegia, myocardial depression, and cytotoxic effects [28]. Nitric oxide has potent antiatherogenic and antiadhesion properties. Nitric oxide effects the upregulation of several endothelial cells, and leukocyte endothelial cell adhesion molecules, including P-selectin, VCAM-1, and CD11b/CD18, modulate the leukocyte–endothelial cell interaction [15, 16]. Therefore, under normal physiologic conditions, NO inhibits leukocyte adhesion to the vascular endothelium [15, 16] and plays a critical role in the regulation of vascular homeostasis and pathogenesis of atherosclerosis [2, 15, 16]. Unfortunately, harvesting and hypoxic storage process reduces endothelial NOS expression, and decreases NO production in HSVGs [2, 3, 12, 17, 18], causing an upregulation of leukocyte adhesion molecules on HSVG endothelial cells [3, 4, 6, 7, 14]. Thatte and coworkers [2] and Thatte and Khuri [3] reported that endothelial cell viability is compromised within minutes of storage in standard preservation solutions and nearly all endothelial cells were nonviable after 1 hour. They also reported that there was a steady and significant decrease in endothelial NOS–dependent NO generation in the course of the preservation period, and after 4 hours of storage, the veins completely lost their ability to synthesize NO [3]. The loss of the ability of endothelial cells to generate NO during the storage period may adversely affect vasoreactivity and graft patency. Therefore, enhancement of endothelial NO synthesis and increased cGMP levels in HSVGs during the storage period may reduce endothelial injury and graft failure after implantation. In this study, we demonstrated that INOS-2 expression and cGMP levels were significantly higher in the resveratrol-preserved HSVGs compared with the control grafts after a 1-hour storage period. There was also a parallel decrease in myeloperoxidase level and adhesion molecule expression, indicating a less pronounced proinflammatory reaction in the resveratrol-preserved grafts. We presume that decreased neutrophil adhesion to the HSVG endothelium and adhesion molecule expression in the resveratrol-preserved grafts might be a consequence of enhanced expression of INOS-2 and cGMP at the corresponding grafts. Furthermore, reduction in myeloperoxidase content, reflecting lesser neutrophil adhesion to the resveratrol-treated graft endothelium, might be secondary to reduction in surface expression of ICAM-1 and VCAM-1 or may also be a direct effect of resveratrol on neutrophils. Unfortunately, this study does not fully elucidate this issue. However, the results of this study confirm that resveratrol provides a favorable environment for venous endothelium and cellular support during ex vivo storage.
Short-term preservation of free vascular grafts in a storage solution is a daily routine in coronary operations. However, the viability of the vessel during ex vivo storage of HSVG is closely dependent on the time of storage and composition of the storage solution [2, 3, 5, 8, 9]. Unfortunately, current preservation solutions, which vary from physiologic salt solutions to heparinized blood, are an important independent contributor of endothelial injury in HSVGs [2, 3, 5, 8, 9]. For example, the currently available solutions lack an energy source, such as glucose, and have a higher acidic state that may be injurious to the fragile endothelial cells [3, 8, 9]. Therefore, they do not represent a physiologic medium sufficient for endothelial cell support [3, 5, 7–9]. Moreover, they are deficient in free radical scavengers, antioxidants, and NOS substrates that might help to sustain endothelial cell function during storage [1, 3, 7–10]. Therefore, it has been speculated that changing the composition of the storage solution may render a long-term protective effect on the HSVG or at least partly ameliorate the observed adverse effects of current preservation solutions [2, 3]. Vural and associates [29] demonstrated that mast cell membrane stabilization might reduce VCAM-1 expression and increase INOS-2 expression in HSVGs after 1 hour of storage. Our findings support that adhesion molecules and INOS-2 expression may become detectable after 1 hour of storage of these grafts.
In conclusion, the antioxidant property of resveratrol and its potential capacity to stimulate endothelial NO production prompted us to investigate the protective effects of resveratrol on the endothelium of harvested saphenous vein grafts. In this experiment, we examined the possibility that increasing antioxidant availability and NOS substrate in the storage solution would prevent hypoxic endothelial injury, restore NO-dependent responses, and provide better endothelial protection. By comparing matched pairs of HSVGs, we demonstrated that a 60-minute storage period with standard storage solution was associated with an increase in expression of endothelial adhesion molecules ICAM-1 and VCAM-1, as well as myeloperoxidase activity. There were also decreased levels of INOS-2 expression and cGMP. In contrast, we demonstrated that resveratrol-treated HSVG segments expressed less ICAM-1, VCAM-1, and myeloperoxidase activity as well as more INOS-2 and cGMP. This may be attributable to either a different mechanism of action for resveratrol in which ICAM-1, VCAM-1, and INOS-2 may be involved, or a possible INOS-2 induction pathway inversely related to ICAM-1 and VCAM-1 receptor activation. Furthermore, the observed results might be a consequence of a direct effect of resveratrol on neutrophils and endothelial cells. However, current data did not provide a scientific explanation for this observation, and further studies in this area are certainly required to extend beyond speculation. Future studies should also focus on measuring cGMP levels when NO is released under increased stimulation as this study was conducted in a baseline, unstressed state. The present data demonstrate that venous endothelium may be activated by the ex vivo storage period, and that the storage period presents an opportunity to modulate vascular properties.
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Acknowledgments
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This study was supported by institutional research funds. Doctor Kaplan was supported by a research grant from the Turkish Ministry of Health.
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Abstract
Introduction
