Published online before print December 29, 2005, doi: 10.1161/01.ATV.0000201932.32678.7e
© 2006 American Heart Association, Inc.
Vascular Biology |
TNF-
Contributes to Endothelial Dysfunction in Ischemia/Reperfusion Injury
From the Departments of Anethesiology, Surgery, and Physiology (C.Z., X.X.), LSU Health Sciences Center, New Orleans, La; the Department of Medical Physiology (W.W., L.K.), College of Medicine, Texas A&M University System Health Science Center, College Station, Tex; the Section of Cardiovascular Sciences (L.M.), Baylor College of Medicine, the Methodist Hospital, and the DeBakey Heart Center, Houston, Tex; and the Department of Physiology (B.J.P., G.J.B., W.M.C.), LSU Health Sciences Center, New Orleans, La.
Correspondence to Cuihua Zhang, Departments of Anesthesiology, Surgery, and Physiology, School of Medicine, LSU Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112. E-mail czhang{at}lsuhsc.edu
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Abstract |
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Background— Despite the importance of endothelial function for coronary regulation, there is little information and virtually no consensus about the causal mechanisms of endothelial dysfunction in myocardial ischemia/reperfusion (I/R) injury. Because tumor necrosis factor-
(TNF-) is reportedly expressed during ischemia and can induce vascular inflammation leading to endothelial dysfunction, we hypothesized that this inflammatory cytokine may play a pivotal role in I/R injury-induced coronary endothelial dysfunction.
Methods and Results— To test this hypothesis, we used a murine model of I/R (30 minutes/90 minutes) in conjunction with neutralizing antibodies to block the actions of TNF-. TNF- expression was increased >4-fold after I/R. To determine whether TNF- abrogates endothelial function after I/R, we assessed endothelial-dependent (ACh) and endothelial-independent (SNP) vasodilation. In sham controls, ACh induced dose-dependent vasodilation that was blocked by the nitric oxide synthase (NOS) inhibitor L-NMMA (10 µmol/L), suggesting a key role for NO. In the I/R group, dilation to ACh was blunted, but SNP-induced dilation was preserved. Subsequent incubation of vessels with the superoxide (O2·–) scavenger (TEMPOL), or with the inhibitors of xanthine oxidase (allopurinol, oxypurinol), or previous administration of anti-TNF- restored endothelium-dependent dilation in the I/R group and reduced I/R-stimulated O2·– production in arteriolar endothelial cells. Activation of xanthine oxidase with I/R was prevented by allopurinol or anti–TNF-.
Conclusions— These results suggest that myocardial I/R initiates expression of TNF-, which induces activation of xanthine oxidase and production of O2·–, leading to coronary endothelial dysfunction.
We examined the role of TNF- in endothelial dysfunction after myocardial ischemia-reperfusion (I/R) injury. I/R injury compromised endothelium-dependent dilation to acetylcholine (ACh). TNF- expression was increased >4-fold after I/R. Anti-TNF- restored vasodilation to ACh and reduced xanthine oxidase activity, the production of O2·–.
Key Words: coronary artery disease • endothelial function • nitric oxide • microcirculation • reactive oxygen species
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Introduction |
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Tumor necrosis factor-
(TNF-) is an inflammatory cytokine1 that is expressed by macrophages and cardiac tissue early during the myocardial ischemia-reperfusion (I/R) injury.2,3 Elevations of TNF- expression also appear to cause cardiomyopathy.4,5 Interestingly, both cardiomyopathy and I/R injury are characterized by endothelial dysfunction, but, a putative role for TNF- in the abnormal vasodilatory responses during I/R has not been elucidated. Studies from our laboratory6 and others7,8 have shown that I/R produces vascular endothelial dysfunction as defined by abrogated endothelium-dependent dilation. This adverse effect on endothelial function can occur acutely6 or chronically (I/R injury in the pig can produce endothelial dysfunction for weeks).9 However, endothelial dysfunction may be amplified by neutrophil-generated factors including oxygen-derived free radicals, cytokines, proteases, and lipid mediators.10 I/R generates high levels of free radicals11 composed of both reactive oxygen intermediates and nitric oxide (NO) via a complex sequence of events. When generated in sufficient concentrations, free radicals directly injure the myocardium and may even cause cell death.12 The production of O2·– is generally accepted as a contributing factor to I/R-induced microvascular injury. In addition, a decrease in endothelium-dependent dilation occurs soon after the generation of O2·– radicals during reperfusion,11,13–15 thus suggesting that endothelial generation of O2·– radicals acts as a triggering mechanism for endothelial dysfunction.
A role for TNF- in myocardial ischemic injury was directly implicated by the work of Heusch and Schulz.16 These investigators observed that in a model of coronary embolization, expression of TNF- produced progressive coronary constriction that exacerbated the initial magnitude of ischemia. Current evidence suggests that TNF- participates in myocardial I/R injury and cardiac allograft rejection.17,18 A mechanism by which TNF- may induce injury pertains to the production of O2·–, but linking TNF- expression to O2·– production and endothelial dysfunction in endothelial injury during I/R has not been previously proposed. The purpose of our study was to determine the role of TNF- in endothelial dysfunction during I/R injury by studying NO-mediated vasodilation to ACh in isolated and pressurized coronary arterioles, O2·– production, activation of xanthine oxidase, and expression of TNF- with and without neutralizing antibodies to TNF-.
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Methods |
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Please see online Material at http://atvb.ahajournals.org.
Data Analysis
At the end of each experiment, the vessel was relaxed with 100 µmol/L SNP to obtain its maximal diameter at 60 cm H2O intraluminal pressure.19,20 All diameter changes in response to agonists were normalized to the vasodilation in response to 100 µmol/L SNP and expressed as a percentage of maximal dilation. All data are presented as mean±SEM. Statistical comparisons of vasomotor responses under various treatments were performed with 2-way ANOVA and intergroup differences were tested with Bonferonni inequality. Significance was accepted at P<0.05.
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Results |
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I/R Increased TNF-
mRNA Expression and Plasma Concentration of TNF- in Murine Coronary ArteriolesFigure 1A shows the expression of TNF-
mRNA (204 bp) in left ventricular coronary arterioles of sham and I/R groups; expression of TNF- was increased >4-fold after I/R. Figure 1B shows the inflammatory cytokine TNF- is significantly increased after I/R (n=4), but anti-TNF- attenuate the concentration of free TNF- in I/R because the bulk of the circulating cytokine is bound to the antibody. However, plasma concentration of IL-6, IL-8, and IFN-
are not increased after I/R (data not shown). Our studies indicated that after I/R, levels of TNF- were the only cytokines to increase (P<0.05).
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Effects of I/R on NO-Mediated Vasodilation to ACh
Isolated murine coronary arterioles from control and sham animals dilated dose-dependently to the endothelium-dependent agonist, ACh (Figure 2A). Administration of the nitric oxide synthase (NOS) inhibitor L-NMMA (10 µmol/L) reduced the vasodilatory responses to ACh compared with controls (Figure 2A). In a similar manner as L-NMMA, ACh-induced vasodilation was impaired after I/R (30 minutes/90 minutes). Function of smooth muscle was preserved, because SNP-induced vasodilation was equivalent in both groups (Figure 2B).
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Role of TNF- in I/R-induced Vascular Dysfunction
Neutralizing antibodies to TNF- (I.P. 0.1 mg/mouse containing 16 mg protein/mL, administered 3 hours before initiating I/R) maintained NO-mediated coronary arteriolar dilation after I/R, but administration of nonimmune IgG did not (intraperitoneal 0.1 mg/mouse containing 16 mg protein/mL, administered 3 hours before initiating I/R) (Figure 3A). Anti-TNF- did not affect dilation in the sham group. We administered TNF- (1 ng/mL, 60 minutes) and assessed responses of microvessels to ACh to show the acute administration of TNF- could mimic the responses of I/R. ACh-induced dilation was significantly blunted by TNF- or L-NMMA, but combined treatment (TNF- plus L-NMMA) did not induce further abrogation of endothelial dilation (Figure 3B).
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Roles of Superoxide, Xanthine Oxidase, Mitochondrial Respiratory Chain, and NAD(P)H Oxidase in I/R-Induced Vascular Dysfunction
Administration of an O2·– scavenger, TEMPOL (Figure 4A; n=7) or xanthine oxidase inhibitor, allopurinol (Figure 4A; n=7), or oxypurinol (Figure 4B; n=4) maintained vasodilation to ACh in I/R, but rotenone or apocynin did not. Furthermore, TEMPOL (data not shown; n=3), allopurinol (Figure 4A; n=4), oxypurinol (Figure 4B; n=4), rotenone (Figure 4C; n=5), or apocynin (Figure 4C; n=4) did not affect ACh-induced vasodilation in sham groups.
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I/R-Induced Superoxide Production in Murine Coronary Arterioles
In control conditions, DHE fluorescence revealed sparse levels of O2·– throughout the vessel wall (Figure 5A). Incubation of arterioles isolated from coronary arterioles of control mice hearts with TNF- (1 ng/mL, 60 minutes) caused a pronounced increase in fluorescent signals in both endothelial and smooth muscle layers, indicating augmented levels of O2·– production in these cell types. I/R also significantly elevated production of O2·– in both endothelial and smooth muscle layers during I/R injury compared with sham control (vehicle). Administration of O2·– scavenger TEMPOL, or allopurinol, or anti-TNF- abolished O2·– production, but apocynin or nonimmune IgG did not (DHE fluorescence; Figure 5A). Figure 5B shows the results from EPR spectroscopy to quantify the production of O2·–. O2·– production increased after I/R compared with the sham group (P<0.05) and, importantly, administration of anti-TNF- reduced the expression of O2·– to the level observed in the sham group.
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I/R Increased Xanthine Oxidase Activity in Murine Coronary Arterioles
Xanthine oxidase activity was measured in isolated coronary arterioles from 6 groups (sham, I/R, anti-TNF- plus sham, anti-TNF- plus I/R, allopurinol plus sham, and allopurinol plus I/R) to investigate the connection between xanthine oxidase and TNF- in I/R-induced endothelial dysfunction (Figure 6). Importantly, this increase in activity was prevented by anti-TNF- or allopurinol to levels similar in the sham group with or without treatments.
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Discussion |
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Our major finding is that antibody neutralization of TNF-
prevented coronary endothelial dysfunction during myocardial I/R injury. We also found that neutralization of TNF- reduced O2·– generation and xanthine oxidase activity during I/R, and blockade of xanthine oxidase mimicked the actions of anti-TNF- on O2·– production and endothelial function. Molecular evidence indicated that the expression of TNF- (mRNA) was significantly increased in I/R injury. These results suggest that myocardial I/R initiates expression of TNF-, which induces activation of xanthine oxidase and production of O2·–, leading to endothelial dysfunction. Our findings support the concept that TNF- plays a pivotal role in endothelial dysfunction during myocardial I/R injury. We believe that our findings further understanding of the mechanism(s) underlying endothelial dysfunction after myocardial I/R injury.
I/R and Endothelium-Dependent Dilation in Murine Coronary Microvessels
The mechanisms of I/R injury are multifactorial and incompletely understood. Previous studies6–8 have shown that I/R produces impaired vascular endothelial function as defined by abrogated endothelium-dependent dilation. This impairment has been attributed to arginase,6 depletion of tetrahydrobiopterin,21 O2·–, cytokines, proteases, and lipid mediators.10 Endothelium-derived NO is an important endogenous vasodilator that regulates microvascular tone. The endothelial release of NO underlies the mechanism of coronary arteriolar dilation to ACh.22,23 The endothelial NO component was evident in the present study because L-NMMA attenuated the ACh-induced vasodilation. Consistent with our previous studies, we show here that ACh evokes dilation of coronary arterioles (probably by activation of endothelial NOS). In the present study, endothelium-dependent ACh-induced vasodilation in mouse coronary artery was impaired after I/R, whereas endothelium-independent SNP-induced vasodilation was normal, and these diminished responses were not further reduced by treatment with a NOS inhibitor, suggesting that I/R produces endothelial dysfunction in a murine model of reperfusion injury. I/R injury is known to induce endothelial dysfunction,21 and our results speak to a causative role for TNF- because anti-TNF- prevented endothelial dysfunction.
The Role of TNF- in Coronary Vascular Function in I/R Injury
Endothelial dysfunction is an important early recurring phenomenon in virtually all forms of I/R injury, including a variety of circulatory shock states.10 The role of TNF- in ischemic injury in the intact heart is controversial with some groups reporting beneficial effects,24,25 whereas others find a detrimental role.26,27 TNF- clearly initiates expression of an entire spectrum of inflammatory cytokines.23,36 Accordingly, we hypothesized that TNF- expressed in the endothelium might play a pivotal role in the regulation of NO-mediated vasodilation by increasing O2·– production, thereby decreasing NO bioavailability. Although we did not unequivocally eliminate a role for other cytokines in I/R injury, our results show that IL-6, IL-8, and INF- were not elevated. Nevertheless, we are compelled in confine our conclusions to the effect of TNF- because we did not systematically study these other cytokines.
A critical issue about our interpretations pertains to the specificity of the anti-TNF-. Within this context, we have made several observations that demonstrate specificity of the antibody.31 Although the antibody is polyclonal, it shows no cross-reactivity with other cytokines.31 The ability of the antibody to bind to a few other recombinant cytokines was tested to a limited degree and we found binding only to murine TNF-.31 The antigen was recombinant murine TNF- and therefore it is very unlikely that this IgG neutralizes other cytokines.31 We used nonimmune control IgG.31 Moreover, in an animal model of lipopolysaccharide (LPS)-induced shock, anti-TNF- completely blocked increases in plasma TNF-, because the antibody bound the cytokine.31 In previous published and unpublished studies, anti-TNF- has not universally attenuated LPS-induced effects on pulmonary parameters.32–35 This means TNF- is not solely responsible for LPS-induced effects, and our antibody does not block whatever it is that causes these effects. Thus, we believe with conviction that the antibody is specific for TNF-, and thus our interpretations and conclusions about the pivotal role this cytokine plays in endothelial I/R injury are correct.
There is no previous report on the endogenous role of TNF- in this respect to our knowledge, and it has been unclear whether TNF- plays a direct role in endothelial dysfunction during I/R injury. In the present study, we documented that TNF- is critical for the development of endothelial reperfusion injury. TNF- expression was significantly increased in murine coronary arterioles after I/R injury; neutralizing antibodies to TNF- restored NO-mediated coronary arteriolar dilation in the I/R group, but did not affect the endothelium-dependent vasodilation in sham controls. To further establish this deleterious role of TNF-, we attempted to mimic the endothelial injury by incubating isolated arterioles with TNF-. A 60-minute incubation of endothelium-intact coronary arterioles with TNF-, which did not alter resting diameter, blunted the ACh-induced vasodilatory response. Thus, TNF- under the conditions of our experimental protocols appears to have a deleterious effect on vascular function by inducing endothelial dysfunction.
One interesting observation was an increase in TNF- expression (4-fold) and an increase in plasma concentration of TNF- (6- fold) after a total of 120 minutes of I/R. Although, we are not sure of the cell type that is expressing TNF-, a component of the signal may be related to infiltrating cells such a macrophages. If TNF- is, as we and others suspect, one of the initiators of a cytokine cascade, then it may also be one of the genes that is induced very quickly after perturbation.
Roles of ROS and Xanthine Oxidase in Coronary Vascular Function in I/R Injury
Endothelial dysfunction appears to occur very early after reperfusion, signaled by the endothelial generation of a large burst of superoxide radicals.14,28 The decrease in endothelium-dependent dilation has been shown to occur soon after the generation of O2·– by the reperfused coronary endothelium,14 suggesting that endothelial generation of O2·– radicals acts as a trigger mechanism for endothelial dysfunction. O2·– also reduces the bioavailability of NO, which would compromise dilation to endothelium-dependent stimuli. Thus, it appears that impaired NO-dependent functions, eg, vasodilation, are the direct result of the overproduction of O2·– during the development of I/R injury. Although many studies document oxygen radical formation during I/R, there is a paucity of knowledge regarding mechanisms responsible for stimulating the production of O2·–. Our results extend this knowledge by demonstrating the role of TNF- in I/R-induced endothelial injury via stimulation of xanthine oxidase to produce O2·– as shown by our observation that anti-TNF- prevented I/R-induced xanthine oxidase activation and O2·– production.
Although there are multiple intracellular sources for formation of oxygen free radicals [eg, mitochondria, NAD(P)H oxidase, etc], our results support the idea that the major enzyme activated by TNF- during I/R is xanthine oxidase. We are not sure that allopurinol, in vitro, is acting as a free radical scavenger; however, we can state with conviction, based on our new results, that allopurinol is inhibiting xanthine oxidase. Our results indicated that the pathway for TNF-–induced endothelial dysfunction is mediated by activation of xanthine oxidase and the subsequent production of O2·–. This idea is supported by the finding of Pereda et al,29 which shows that simultaneous inhibition of TNF- production and xanthine oxidase activity greatly reduced local systemic inflammatory response in acute pancreatitis.29 Our study shows that I/R injury increased the xanthine oxidase activity, and antibody to TNF- and xanthine oxidase inhibitor, allopurinol, separately attenuated the xanthine oxidase activity in I/R injury. In the majority of studies cited pertaining to reperfusion injury, elevations in O2·– production are thought to be a critical factor in this process. Our results demonstrate the production of TNF- is essential in eliciting this oxidative stress. The present study indicates that I/R increases TNF-, which stimulates endothelial generation of O2·– through activation of xanthine oxidase in the endothelium and contributes to the endothelial dysfunction. To our knowledge, this is the first functional study to link the mechanism(s) of I/R injury—in terms of endothelial dysfunction—to TNF-, the subsequent activation of xanthine oxidase, and thus the production of O2·– in coronary arteriolar endothelium. One caveat: we studied the role of TNF- in endothelial dysfunction only in an acute setting. The chronic endothelial injury that occurs for weeks after I/R9 may be the result of a different mechanism. The study of this effect deserves further investigation.
In conclusion, our results demonstrate that the endothelial dysfunction occurring subsequent to I/R injury is caused by TNF-, which induces activation of xanthine oxidase and production of O2·–. We speculate that many conditions with a moderate elevation of TNF-, eg, septicemia, acute myocardial infarction, chronic heart failure, atherosclerosis, viral myocarditis, and cardiac allograft rejection18,30 may potentially mitigate the role of NO in coronary flow regulation and thus contribute to further deterioration of cardiac function. Selective modulation of xanthine oxidase signaling may provide a novel therapeutic target to prevent or alleviate coronary diseases associated with TNF- activation.
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Acknowledgments |
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This study was supported by grants from American Heart Association grant-in-aid (0455435B), Atorvastatin Research Award (2004-37), American Heart Association SDG (110350047A) to Dr Zhang, National Institutes of Health grants COBRE (P20 RR18766) to Dr Lanier, and National Institutes of Health grants (HL32788, HL65203) to Dr Chilian. We thank Drs Arthur M. Feldman, Steven Lanier, Michael Davis, Jay D. Humphrey, and Mark Entman for their expert assistance.
Received October 5, 2005; accepted December 14, 2005.
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