Alcohol and Alcoholism Vol. 37, No. 6, pp. 555-560, 2002
© 2002 Medical Council on Alcohol
ETHANOL MODULATES CORONARY PERMEABILITY TO MACROMOLECULES IN MURINE AIDS
1 Divison of Health Prevention Science, College of Public Health and
2 Cardiovascular and Thoracic Surgery and The Sarver Heart Center, School of Medicine, University of Arizona, Tucson, AZ 85724, USA
Received 17 January 2002;
first review notified 10 May 2002; first review notified 5 June 2002;
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ABSTRACT |
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 TOPFOOTNOTES ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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— Background and Aims: The cardiovascular complications of AIDS are serious. However, the underlying mechanisms are unclear. Less is known about how ethanol affects the coronary microcirculation in individuals with AIDS. The aim of this study was to assess the integrity of the coronary microcirculation in murine AIDS mice in the presence or absence of chronic ethanol consumption. Methods: Four groups were studied: control, murine AIDS, ethanol and ethanol plus murine AIDS. Mouse hearts were prepared for direct visualization of the coronary microcirculation and quantification of trans-coronary macromolecular leakage. Hearts were isolated and perfused with diluted rat blood containing fluorescein isothiocyanate–albumin (FITC–BSA). Coronary vessels were observed using intravital fluorescence microscopy after 5, 15 and 25 min of perfusion. The mean luminosity of outside/inside coronary vessels (O/I ratio) was used to quantify FITC–BSA leakage. Results: We found that the mean O/I ratio for the murine AIDS group was significantly greater than in the control group and also significantly increased during the perfusion period. Chronic ethanol consumption did not alter coronary permeability to macromolecules, but improved the coronary haemodynamics in murine AIDS. Conclusions: These findings suggest that murine AIDS impairs the structural and functional coronary endothelium, and moderate ethanol consumption modulates the function of the coronary microcirculation.
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INTRODUCTION |
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The World Health Organization (WHO) estimated that AIDS is affecting more than 60 million people worldwide. HIV cardiomyopathy is the fourth leading cause of dilated cardiomyopathy in the United States. Congestive heart failure has become the leading cause of death in paediatric patients with AIDS, and half of the children die within 6–12 months (Johann-Liang et al., 1997
). Coronary microvascular endothelial dysfunction may contribute to cardiovascular involvement in AIDS. There are no reports on the effect of AIDS on the integrity of the coronary microcirculation. Indirectly, several studies report that the retrovirus impairs the blood–brain barrier (Glass and Johnson, 1996; Pereira et al., 2000; Persidsky et al., 2000). In this study, we tested the hypothesis that endothelial function is altered in AIDS, causing increased coronary microvascular permeability to macromolecules.
Alcohol misuse has a negative impact on human health. However, the relation of alcohol intake to mortality resembles a J-shaped curve. The higher the intake, the higher the mortality, with the exception that abstainers have higher mortality than moderate drinkers (Poikolainen et al., 1996). Epidemiological studies reported that moderate consumption of ethanol reduces the risk of coronary heart disease, sudden cardiac death, and ischaemic stroke (Stampfer et al., 1988; Iso et al., 1995; Poikolainen et al., 1996; McKee and Britton, 1998; Van Tol and Hendriks, 2001). It is seen that regular moderate drinking tends to have a beneficial effect on the heart. The mechanisms for cardiovascular protective effects are not well established. We propose that moderate ethanol consumption could modulate coronary microvascular function.
Fourteen per cent of HIV-infected patients misuse alcohol (Welch, 2000). Moderate ethanol intake may modulate cardiovascular alterations in AIDS. In this study, we therefore investigated the combined effects of AIDS and ethanol consumption on coronary microvascular integrity.
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MATERIALS AND METHODS |
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Animals
Female C57BL/6N mice (National Cancer Institute) at 8–12 weeks of age and weighing about 20–22.5 g were randomly assigned to four different groups: control, murine AIDS, ethanol and murine AIDS plus ethanol. Mice were housed in transparent plastic cages with a stainless wire lid in a room at 20–22°C with constant humidity (60–80%) and a 12 h:12 h light–dark cycle (lights on at 07.00). Murine AIDS was induced by LP-BM5 murine leukaemia retrovirus infection. The LP-BM5 viruses were administered intraperitoneally (i.p.), as done previously by our laboratory (Chen and Watson, 1991
; Wang et al., 1994; Watson et al., 1995). In the first week, 10% (v/v) ethanol in autoclaved tap water was made available to the chronic ethanol group mice in a 300-ml plastic bottle with a stopper. The ethanol concentration increased to 20% (v/v) in the second week and was kept at 20% (v/v) for the rest of the treatment periods. The average ethanol intake per mouse was 2.8 ml/day. Mice were active at night; therefore, we took blood samples at night (3.5 h after lights were turned off) to estimate blood-ethanol concentration (Sigma Diagnostics Alcohol Kit). The average blood-ethanol concentration was 66.9 mg/dl (0.0669%). The non-ethanol fed mice were given the same diet, except that the water bottles contained pure water. No weight loss was found at the end of the experimental period between the non-ethanol and ethanol-fed mice.
Heart isolation
The animal model used to directly visualize coronary microcirculation is a modified Langendroff heart preparation (McDonagh, 1983). The procedure is as follows: After 3 months of intervention, mice were anaesthetized with sodium pentobarbital (55 mg/kg i.p.). The abdomen was opened to expose the abdominal aorta. Immediately, a PE 10 catheter was inserted and advanced to the aortic arch. The vena cava was then cut and cold cardioplegic solution (Abbott’s Cardioplegic Solution for Cardiac Perfusion) was injected immediately through the catheter to arrest and protect the heart. After the heart stopped beating, a medial sternotomy was rapidly performed to expose the heart. Loose ligatures were placed around the right innominate artery and ascending aorta. Heparin (15 U) was injected into the right atrium. The ligatures around the subclavian and common carotid arteries were tied, and a PE 50 catheter was inserted into the innominate artery. The catheter was advanced toward the heart, until the tip extended just into the aorta. The catheter was secured and connected to the extracorporeal perfusion system. A small hole was cut in the right atrium. The aortic ligature was tied quickly, ensuring that all perfusate flow was retrograde to the coronary circulation. Then, the heart was removed from the thoracic cavity and placed on a heated Lucite stage for intravital fluorescence microscopy of the left ventricular epicardial microcirculation. The isolated hearts were perfused with a physiological solution that maintained normal cardiac and normal coronary microvascular functions.
Preparation of diluted whole blood for perfusate
Donor rats (450–500 g) were anaesthetized with ether, and 6 ml of arterial blood were withdrawn immediately into a heparinized syringe via cardiac puncture. The rat blood was then diluted 1:1 with Krebs-bicarbonate solution. A small aliquot of diluted whole blood was used to measure pH, PO2, PCO2, haematocrit (Hct), leucocyte and platelet counts. Typical values obtained from the diluted whole blood were: pH 7.37–7.45, PO2 100–125 mmHg, PCO2 30–40 mmHg, Hct 21%, leucocyte counts 5.2 x 103/µl, platelet counts 2.0 x 105/µl.
Preparation of fluorescein isothiocyanate (FITC)–BSA
The preparation was described previously (McDonagh and Williams, 1984). The FITC was first conjugated to albumin as follows: 1.25 g of albumin were dissolved in 18.75 ml of carbonate-bicarbonate buffer (CBB, pH 9.0). In a glass beaker, 0.0625 g of FITC were added to 6.25 ml of CBB and stirred until the FITC was completely dissolved. The albumin/CBB and the FITC/CBB solution were then mixed and covered with foil. The mixture was stirred at a slow speed overnight at 4°C. The following day, 25 ml of FITC–BSA was run down a Sephadex column (Sephadex G-25, medium, Amersham Pharmacia Biotech; 100 ml Cap. Aldrich Flash-Chromatography Columns) to separate the conjugated from unconjugated FITC. Fifteen millilitres of conjugated FITC were collected and concentrated with an Amicon Centriprep (molecular weight cut-offs 10 kDa). The final conjugated FITC–BSA solution was poured into a sterile tube, bringing the total volume up to 10 ml with sterile phosphate-buffered saline.
Measurement of coronary microvascular permeability to macromolecules
The isolated perfused mouse heart was oriented on the microscope stage with the free wall of the left ventricle facing up. A large coronary vein that courses along the left ventricle from apex to base was used to orient the heart on the stage. The aortic catheter was then connected to the syringe pump containing the perfusate. The coronary perfusate consisted of a mixture of 47.5% fresh whole rat blood obtained by cardiac puncture from a donor rat, 47.5% Krebs-BSA and 5% FITC– BSA. The [K+] of the final perfusate solution was 30 mM, to ensure cardiac arrest while observing the coronary microcirculation. The perfusate blood gas was measured before perfusion. During constant flow perfusion at a flow rate of 0.3 ml/min, the coronary perfusion pressure was monitored (Pressure Monitor BP-1) via a sideline.
Five coronary microvascular fields were observed after 5, 15 and 25 min of perfusion using intravital fluorescence microscopy (Ritter and McDonagh, 1997). Venular fields were brought into clear focus and videotaped at each time point. After 30 min of observation, the perfusion was stopped. The videotaped results were analysed using Dazzle DVC and Adobe software (Adobe Photoshop 5.5). Five to six fields/heart/ time points were determined for the O/I ratio. The O/I ratio was used to quantify transcoronary FITC–BSA leakage (Fig. 1).
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Statistical analysis
Statistical analysis was performed using SPSS Statistical software (SPSS Windows 10.0). Comparisons among the groups were made by analysis of variance (ANOVA). If significant differences were observed, Newman–Keuls post hoc testing was performed. To compare data as a function of time, we used repeated ANOVA.
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RESULTS |
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Coronary vascular resistance
Table 1
summarizes the coronary vascular resistances of the four groups throughout the experiment. The initial coronary resistance was quite similar among the control, ethanol and murine AIDS plus ethanol groups. Coronary resistance was relatively consistent over the perfusion period in these groups. In murine AIDS, however, the initial value was slightly increased, but no significant difference was found when compared to the other three experimental groups. Thereafter, the coronary resistance increased with perfusion. We also observed that, in two of six hearts from this group, coronary perfusion pressure suddenly increased to 200 mmHg toward the end of the perfusion period. A few minutes later, a marked increase (O/I 
1) in transcoronary protein extravasation was observed.
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Coronary permeability to macromolecules
All four groups of hearts were perfused at the same flow rate of 0.3 ml/min and the same FITC–BSA delivery rate. The duration of exposure to the excitation light was the same for all groups. Five fields were observed at each perfusion time to limit the differences in fluorescence background. As Fig. 2
demonstrates, in the control group the O/I values were relatively constant over the perfusion period. A repeated ANOVA indicated that the O/I ratio did not significantly increase with time. In the murine AIDS mice, we observed some extravasation of FITC–BSA in the first 5-min period of perfusion (O/I = 0.77 ± 0.03). Compared to the control group at the same time point, the increase was significant (P < 0.05). In addition, one or two severe, more localized ‘leaky spots’ of FITC–BSA were observed in three out of six murine AIDS hearts (Fig. 3D). This phenomenon was not observed in the control mice. Upon perfusion, resolution of the microvessels was reduced markedly as the FITC–BSA diffused in the extravascular space. Extravasation continued with time in the murine AIDS mice, and, after 25 min of perfusion, the O/I reached 0.95 ± 0.02. Because FITC–BSA accumulation in the extravascular space was marked at this time, it was occasionally difficult to find the same capillary-venular fields chosen at the initial reading. Overall, the O/I ratio in the murine AIDS mice (Figs 2 and 3) was significantly increased compared to the control group at each time point and significantly increased as a function of time (P < 0.001).
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Chronic ethanol consumption did not alter coronary microvascular permeability to albumin compared to control mice. The O/I ratio did not significantly change during the perfusion periods. The coronary microvascular barrier to albumin was maintained over the perfusion time. In murine AIDS plus ethanol-consuming mice, the O/I values were not significantly different as a function of perfusion time. However, compared to the control at each perfusion period, murine AIDS plus ethanol-consuming mice demonstrated significant transcoronary protein extravasation in the initial perfusion period (P < 0.05), maintained no significant change during 15–20 min of perfusion and then increased again during 25–30 min of perfusion. Chronic ethanol consumption did not completely reverse the effect of murine AIDS on coronary permeability to macromolecules but modulated changes in coronary haemodynamic parameters.
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DISCUSSION |
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TOPFOOTNOTESABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Coronary microvascular endothelial dysfunction may contribute to cardiovascular complications in AIDS. We were interested in observing a significant increase in coronary microvascular permeability to macromolecules in murine AIDS mice. These findings suggest that murine AIDS impairs the normal integrity of the coronary microcirculation. The possible mechanisms include: (1) retroviruses directly attack cardiovascular endothelial cells; (2) elevated tumour necrosis factor
(TNF) and platelet activation factor (PAF) released by virus-infected cells are cytotoxic to endothelial cells; (3) overproduced reactive oxygen and nitrogen species by oxidative stress amplify the endothelial cell dysfunction (Adamson et al., 1996; Barbaro et al., 1999). The direct effect of the retrovirus on cardiovascular endothelial cells has not been reported. However, certain endothelial cells, such as those lining liver sinusoids, human umbilical vein endothelial cells, bone marrow stromal endothelial cells or brain microvascular endothelial cells, have been found to be variably permissive for HIV infection (Chi et al., 2000). Zietz et al. (1996) also reported that the aortic endothelial cell pattern in HIV-1-infected patients was clearly disturbed. Overall, these observations indicate that retrovirus may directly attack the vascular endothelium. Our laboratory (Chen and Watson, 1991; Wang et al., 1994; Watson et al., 1995) and others (Giese et al., 1996; Xi et al., 1998) found that retrovirus infection stimulated TNF production. TNF might unzip tight conjunctions between endothelial cells, causing macromolecular movement into the extravascular space. TNF may disrupt the integrity of the coronary vascular endothelium by this cytotoxic mechanism. Recently, in vitro data suggested that TNF-programmed apoptosis is enhanced by PAF receptor activation (Westmoreland et al., 1996; Schifitto et al., 1999). PAF, a versatile lipid inflammatory mediator, is also elevated by retrovirus infection (Gelbard et al., 1994; Westmoreland et al., 1996; Sei et al., 1997; Schifitto et al., 1999; Serradji et al., 2000). PAF may not only act as an apoptotic cofactor, but may also stimulate neutrophils and platelets to form aggregating plugs in the microcirculation. Mechanical obstruction would increase the coronary resistance and further impair cardiovascular performance. Cardiovascular endothelial damage in murine AIDS might also be affected by free radicals. Cell death in culture paralleled increased nitric oxide (NO) (Pinsky et al., 1995) and reactive oxygen species (ROS) (Lin et al., 2000). Viral replication and cytokine stimulation in AIDS are oxidative signals (Floyd et al., 1999; Mollace et al., 2001). No direct evidence exists to verify increased NO and ROS production by cardiovascular endothelial cells in LP-MB5-infected mice, but overproduced NO by induced nitrogen oxide synthase (Barbaro et al., 1999) and ROS by circulating neutrophils (our unpublished data) may rapidly diffuse into coronary vascular endothelial cells to cause endothelial dysfunction in AIDS. Therefore, retrovirus-induced cytokine dysregulation may trigger cardiovascular endothelial cell apoptosis and exaggerate coronary haemodynamics.
Epidemiological studies demonstrate a significant protective effect of moderate alcohol consumption on the incidence of cardiovascular diseases. Possible mechanisms to explain the cardioprotective effect of ethanol are vascular relaxation, HDL elevation, lowering fibrinogen level, modulating platelet function, and anti-thrombotic properties (Redmond et al., 2000; Van Tol and Hendriks, 2001). Recently, Arbabi et al.(1999) found that ethanol inhibited proinflammatory cytokine, TNF and IL-8, secretion. A lower level of proinflammatory cytokines reduces their stimulating effect on neutrophils and platelets. Preventing chronic neutrophil and platelet activation benefits the coronary microcirculation. Ethanol also suppresses cytokine-induced iNOS expression (Syapin et al., 2001), which may involve a mechanism of cardiovascular endothelial cell apoptosis. In addition, ethanol is a vaso-relaxant (Fitzpatrick et al., 1993). This effect may be related to ethanol increasing both vascular endothelial growth factor mRNA expression and protein expression (Gu et al., 2001). Overall, the cardiac protective effect of moderate ethanol consumption may be mediated by cytokine modulation and vaso-relaxation. In our study, chronic ethanol consumption alone did not alter coronary permeability to macromolecules. When murine AIDS mice were exposed to ethanol, coronary resistance was consistently maintained over the entire perfusion period even though coronary permeability increased. These results suggest that chronic ethanol consumption may mainly modulate the coronary haemodynamic function. However, ethanol did not reduce the damage to the coronary microvascular barrier to macromolecules caused by retrovirus infection.
In summary, altering coronary microvascular integrity may contribute to cardiovascular complications of AIDS. The structural and functional changes in the cardiovascular endothelium lead to increased coronary permeability to macromolecules. The retrovirus may directly or indirectly perturb the integrity of coronary endothelium. Chronic moderate ethanol consumption may be cardioprotective but did not reduce the structural destruction by the retrovirus.
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ACKNOWLEDGEMENTS |
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This research was supported by NIH grants HL 63667 and 59794.
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FOOTNOTES |
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* Author to whom correspondence should be addressed at: Division of Health Prevention Science, College of Public Health, University of Arizona, PO Box 245155, Tucson, AZ 85724, USA.
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