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Ann Thorac Surg 2001;71:226-232
© 2001 The Society of Thoracic Surgeons
a Department of Thoracic Surgery, Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
b Cardiovascular Research Unit, Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
Accepted for publication May 8, 2000.
Address reprint requests to Dr Valen, Crafoord Laboratory of Experimental Surgery, L6:00, Karolinska Hospital, S-17176 Stockholm, Sweden
e-mail: guro.valen{at}cmm.ki.se
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Abstract |
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Methods. Gene expression of cytokines, adhesion molecules, and vasoactive substances was evaluated in left ventricular biopsies taken before cardioplegia (lasting approximately 70 minutes) and after reperfusion (approximately 40 minutes) from 19 patients (5 with valvular or combined disease, 7 with stable angina pectoris, 7 with unstable angina). mRNA was extracted and amplified with a semiquantitative reverse transcription polymerase chain reaction.
Results. Cardioplegia-reperfusion increased mRNA for E-selectin by a factor of 17 ± 5 (p < 0.002) (mean ± SEM), interleukin-1ß with 9 ± 3 (p < 0.007), tumor necrosis factor-
with 6 ± 3 (p < 0.05), interleukin-2 receptor chain CD25 with 2 ± 0.6 (p < 0.04), and intercellular adhesion molecule-1 with 2 ± 0.4 (p < 0.005). Before cardioplegia, mRNA for endothelial nitric oxide synthase was predominantly detected in unstable angina patients, and increased by a factor of 11 ± 6 (p < 0.02) during reperfusion. mRNA for endothelin-1 decreased by a factor of 0.5 ± 0.1 (p < 0.0005). The changes were more pronounced in unstable patients. The transcription factor nuclear factor kappa B (NF
B), which regulates expression of inflammatory mediators, was activated during reperfusion (n = 10, p < 0.0001).
Conclusions. Open heart surgery induces an inflammatory response in the human heart, which is more pronounced in patients with unstable angina. It involves NFB activation and expression of several NFB-regulated genes.
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Introduction |
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Evidence suggests that a local inflammatory response is induced in ischemia-reperfusion injury. In the human heart, production of reactive oxygen intermediates and lipid peroxidation products is accompanied by intracoronary release of proinflammatory cytokines and vasoactive substances [1–3]. Activated leukocytes are trapped in the coronary circulation, microvascular permeability is increased, and the reperfused myocardium is ultrastructurally damaged [1–3]. A major feature of reperfusion injury is impaired endothelium-dependent relaxation [2]. It is difficult to distinguish which factors result from local events in the cardioplegic-reperfused heart, and which result from the "whole-body inflammatory response" induced by the CPB from activation of blood components upon contact with foreign surfaces [4]. With the development of the sensitive techniques of molecular biology, the questions of cardiac versus systemic effects or more delayed consequences of reperfusion may be resolved.
The present study investigates the possible inflammatory effects of CPB, cardioplegia, and reperfusion in the human heart during open heart surgery. To characterize the early phase of the inflammatory response, gene expression of mediators influencing vascular tone, leukocyte adhesion, and activation, as well as proinflammatory cytokines, were investigated by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) in left ventricular biopsies. Specifically, gene expression of endothelial and inducible nitric oxide synthase (eNOS and iNOS), the vasoconstrictor endothelin-1 (ET-1), the leukocyte adhesion molecules E-selectin (CD62E), and intercellular adhesion molecule-1 (ICAM-1) were studied [5]. The cytokines tumor necrosis factor- (TNF) and interleukin-1ß (IL-1ß) were included [5]. The leukocyte activation markers CD18 (a ß2 integrin, ligand for ICAM-1) and CD25 (IL-2 receptor chain on activated mononuclear cells) were also investigated to determine whether increased adhesion of activated leukocytes could be a source of inflammatory mediators. To determine mechanisms of gene activation, the redox-sensitive transcription factor nuclear factor kappa B (NFB) was investigated by electrophoretic mobility shift assay in nuclear extracts of atrial biopsies [6].
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Material and methods |
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Tissue sampling
Immediately after start of CPB, but before cardioplegia, a biopsy was taken from the lateral wall of the left ventricle close to the apex with a through-cut biopsy needle (MN1416 diameter 2.1 mm; BIP Gmbh, Turkenfeld, Germany). The amount of tissue obtained by this method is small and allows extraction of mRNA, but is not sufficient for supplementary measurements such as corresponding protein or histology. As long as possible after aortic declamping, immediately before weaning the patient off CPB, another biopsy was taken from the left ventricle close to the site of the first biopsy (Table 1). Additional biopsies (1.0 x 0.5 cm) were collected from the right atrial auricle before cardioplegia and from the left atrial auricle during reperfusion for electrophoretic mobility shift assay (EMSA). Twelve patients were sampled for EMSA, including 2 control patients with concomitant sampling of left and right atrial tissue before cardioplegia to evaluate possible differences between the right and left auricle. All biopsies were collected in sterile, RNase-free tubes, immediately frozen in liquid nitrogen in the operating theater, and stored at -80°C.
RT-PCR
The procedure for mRNA extraction, cDNA synthesis, and semiquantitative PCR is described in detail elsewhere [7]. Briefly, frozen tissue was homogenized in a microdismembrator, and mRNA extracted using a Dynabeads mRNA direct kit (Dynal A.S., Oslo, Norway). Single-stranded cDNA synthesis was performed by Superscript II (Life Technologies, Paisley, UK) according to the manufacturer, using random hexamers (Life Technologies) as primers in the presence of RNasin (Promega, Madison, WI).
All genes in 1 patient were investigated in the same PCR reaction, at a volume of 25 µL for each gene. A master mix consisting of dNTP (6.25 mmol/L), MgCl2 (1.5 mmol/L), PCR buffer, 0.02 U Taq polymerase (all Life Technologies), and 5 µCi [33P]dATP (NEN, DuMedical, Scandinavia) was prepared, and divided in two for addition of cDNA. Samples were aliquoted in separate PCR tubes, and primers added in a final concentration of 0.2 µmol/L using histone H3 as a housekeeping gene. For information on primers and annealing temperatures, see reference 8. For all genes, the relationship between number of PCR cycles and amount of PCR products was evaluated and plotted to determine the linear phase of the amplification reaction as described previously [7]. For H3, 22 cycles were selected; for TNF, IL-1ß, CD18, CD25, and ICAM-1, 26 cycles; for iNOS, 30 cycles; and for ET-1, eNOS, and E-selectin, 32 cycles were used. A control PCR of mastermix without cDNA and with the H3 primer was routinely done in all samples, whereas control reactions on RNA were performed randomly to evaluate possible contaminations. All PCR reactions were run at least twice, and the mean value was employed for further evaluation.
A radiolabeled DNA ladder was synthesized using the Gibco 100-base pair DNA ladder and T4 DNA polymerase kit according to the manufacturers’ description (Life Technologies), with [33P]dATP as the incorporated marker. The PCR products were separated by electrophoresis on a 5% polyacrylamide gel and analyzed in a phosphoimager (BioImaging Analyzer System BAS 1000; Fuji, Stockholm, Sweden). The ratio between optical density of H3 and test gene was calculated to evaluate relative changes in the test gene.
Preparation of nuclear extracts
Atrial tissue was thawed on ice and homogenized in lysis buffer containing 10 mmol/L Hepes (pH 7), 10 mmol/L KCl, 1.5 mmol/L MgCl2, 1 mmol/L protease inhibitor phenylmethylsulfonyl fluoride, and 0.4% Nonidet P-40. After centrifugation at 5,000 g (4°C) for 1 minute, the homogenates were resuspended in lysis buffer and kept on ice for 10 minutes. They were washed with 0.02 mmol/L KCl buffer and centrifuged again. One part 0.02 mmol/L KCl and one part 0.6 mmol/L KCl were added to the pellet and kept on ice for 45 minutes. The supernatant was collected as nuclear extract, and protein content was determined using the bicinchonic acid reagent (Pierce, Rockford, IL).
Electrophoretic mobility shift assay
Nuclear extracts (16 µg protein) were preincubated for 10 minutes in binding buffer (20 mmol/L Hepes, pH 7.9, 5% glycerol, 5 mmol/L MgCl2, 0.5 mmol/L EDTA, and 1 mmol/L dithiothreitol), followed by 30-minute incubation in room temperature with 50,000 cpm of 32P-labeled probe containing the NFB binding site 5' AGT TGA GGG GAC TTT CCC AGG C (Promega). DNA-protein complexes were subjected to electrophoresis on a 4% polyacrylamide gel. For supershift analysis, rabbit polyclonal anti-p65 and anti-p50 antibodies (Santa Cruz Biotechnology, Santa Cruz, CA) were incubated with the binding buffer for 15 minutes before adding the radiolabeled probe. Cold probe competition was performed using a 25- or 50-fold excess of unlabeled probe, whereas unspecific binding was evaluated by employing a 25- to 50-fold excess of the Promega AP-1 probe. The densities of 10 NFB bands taken before cardioplegia and after reperfusion were determined with Tina 2.0 software (Strauberhardt, Mannheim, Germany) after scanning in Adobe Photoshop 7.0.
Calculations and statistics
The factor change (F) of gene expression was calculated as the ratio of the test gene/H3 after cardioplegia (TA/H3A) divided by the ratio of the test gene/H3 before cardioplegia (TB/H3B): F = TA/H3A/TB/H3B. Delta (
) increase was calculated as the difference in ratio before and after (TA/H3A - TB/H3B), and employed for simple regression analysis against time on cardiopulmonary bypass, aortic cross-clamping, and reperfusion. A Student’s t test was used to evaluate differences between samples. A p value less than 0.05 was considered significant. Data are presented as mean ± SEM.
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Results |
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Upregulation after cardioplegia and reperfusion
Gene expression of inflammatory mediators in human heart biopsies were evaluated with a semiquantitative RT-PCR, where all genes were measured relative to a reference gene. Results from a patient with unstable angina are shown in Figure 1. When comparing gene expression in left ventricular biopsies before and after cardioplegia, significant increases were found in mRNA for CD62E (with a factor of 17 ± 5, p < 0.002), IL-1ß (factor 9 ± 3, p < 0.007), TNF (factor of 6 ± 3, p < 0.05), CD25 (2 ± 0.6, p < 0.04), and ICAM-1 (2 ± 0.4, p < 0.005) (Fig 2). eNOS was only detected in patients with unstable angina or combined coronary and valvular disease (nos. 8 and 12 in Table 1) and increased during reperfusion with a factor of 11 ± 6 (p < 0.01). iNOS and CD18 increased with factors of around 2, but this was not significant. ET-1 was downregulated with a factor of 0.5 ± 0.1 (p < 0.0005) (Fig 2). No significant correlations were found between increase of gene expression and duration of CPB, duration of cardioplegic arrest, or time of reperfusion.
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increased in unstable patients (p < 0.04) but did not significantly increase in stable patients, whereas the decrease of ET-1 was significant in unstable (p < 0.04) but not stable patients (Fig. 3). mRNA for ICAM-1, CD18, CD25, and iNOS were more similar between groups. eNOS was not detected in patients with stable angina or single-valve disease, whereas all patients with unstable angina expressed eNOS before and after reperfusion (p < 0.003). eNOS mRNA increased during reperfusion in unstable patients but was not detected in stable patients (Fig 3).
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BB activation in the right and left atrium before start of cardioplegia (n = 2, not shown). Nuclear translocation of NFB was found during reperfusion as evaluated by EMSA. Figure 4 shows a polyacrylamide gel with nuclear extracts from right and left atrial biopsies taken from 2 patients before cardioplegia (B), and after reperfusion (A). Before cardioplegia, only trace amounts of NFB were found. After reperfusion, NFB was activated, as evidenced by increased retardation of the DNA probe containing the NFB motif (Fig 4). The identity of the proteins bound to the probe were determined by supershift analysis with p50 and p65 antibodies. The antibody specific for the p50 subunit of the NFB heterodimer caused further retardation of the mobility of the DNA probe, whereas a small shift was also seen with the p65 probe, indicating that p65/p50 dimers constituted the NFB transcription factors in the heart biopsies. Cold probe competition abolished the band, whereas the AP-1 probe did not influence it, further identifying the bands as NFB (Fig 4). When optical densities of NFB bands of 10 patients before cardioplegia and after reperfusion were calculated, a significant activation of NFB during reperfusion was found (p < 0.0001; Fig 5).
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Comment |
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and IL-1ß, as well as the IL-2 receptor CD25 were all significantly increased. The expression of these genes could be explained by activation of the common transcriptional inducer NFB, because they all have NFB-binding motifs in their promoter regions [6]. Other transcription factors not measured in the present study may have interacted in the up- or downregulation.
NFB is present in cytosol as an inactive heterodimer most often consisting of the p65/p50 subunits, bound to the IB inhibitor. Upon stimulation, it will dissociate from the inhibitor and translocate to the nucleus, where it binds to specific promoter elements and initiates transcription of a set of genes involved in inflammation [6, 8]. The subunit composition of the dimer may determine the precise genes activated by the transcription factor, as may the number of motifs in the genes’ promoter/enhancer regions. Using supershift analysis, we could identify the p50 and p65 polypeptides in nuclear NFB of the reperfused human heart. NFB can be activated by reactive oxygen intermediates as well as proinflammatory cytokines [6]. These factors are generated and released both from the cardioplegic-reperfused heart [2, 3] and by the general inflammation induced by the CPB [4]. Myocardial ischemia-reperfusion-induced NFB activation has previously been described in experimental studies under normothermic conditions [9], and cell culture studies have shown nuclear translocation of NFB at temperatures as low as 17°C [2]. The current study clarifies that ischemia/reperfusion of the human heart indeed elicits NFB activation with ensuing expression of inflammatory genes. However, whether this resulted from cardioplegia reperfusion only or also influenced by factors in blood activated by the CPB is not determined.
Although the investigated genes are regulated by NFB, their expression was unequally induced. The increases in mRNA for iNOS and CD18, which both contain NFB promoter elements, were modest and not statistically significant. This could reflect differential regulation of the different genes. For instance, the induction of ICAM-1 is more delayed than that of CD26E [5, 8], and iNOS induction requires several hours [10]. The heterogenous response of NFB-regulated genes may therefore reflect the short observation time before taking biopsies; in the present time frame, transcription is presumably only at a beginning, with full upregulation to appear at a time point when collection of cardiac biopsies is practically and ethically difficult. Additionally, other transcription factors working in concert with NFB may have been activated and contributed to regulation of gene transcription.
The induction of genes encoding adhesion molecules as well as cytokines is characteristic for inflammatory responses. Because adhesion molecule expression promotes the recruitment of cytokine-producing leukocytes and both TNF- and IL-1ß induce adhesion molecule expression via NFB activation, this pattern of gene expression is likely to operate in positive feedback loops [6]. CD62E is induced by a variety of inflammatory stimuli, and serves as a marker of endothelial activation [5]. In accordance with the present study, its mRNA increased in atrial tissue of children undergoing open heart surgery with cardioplegia-reperfusion [11]. Transendothelial recruitment of leukocytes depends on a concerted action involving selectin-dependent rolling followed by integrin-dependent firm adhesion. The more modest increase in mRNA for ICAM-1 could reflect a situation at the initiation rather than the peak of leukocyte recruitment to the reperfused heart. The small increase of CD25 mRNA makes it unlikely that the cytokine mRNA detected in the tissue was derived from leukocytes to any substantial extent. Instead, it is likely that the increases of mRNA for TNF and IL-1ß as well as nuclear NFB reflected inflammatory activation in cardiomyocytes and other resident cells of the left ventricle.
Tissue injury and inflammation induce profound effects on the local regulation of blood flow. We observed a 10-fold increase in eNOS and mRNA during reperfusion (14-fold in unstable patients). This is likely to result in a substantial increase in the NO-producing capacity, although the ensuing NO production is also determined by a series of posttranslational events [12]. The molecular mechanism causing eNOS mRNA expression in the reperfused heart might be related to the drastic changes in blood flow in conjunction with cardioplegia and reperfusion, which could activate shear stress response elements in the eNOS promoter [13]. Interestingly, eNOS mRNA was detectable only in the hearts of patients with unstable angina or combined disease, but not in stable angina. Accordingly, we have recently found eNOS protein to be upregulated in atrial biopsies of patients with unstable angina [14].
Experimental studies have demonstrated induction of iNOS in injured arteries [15] and ischemic-reperfused hearts [9]. Surprisingly, the increase in iNOS mRNA observed in the present study was small and insignificant. This could result from the short observation time: although the iNOS promoter contains several NFB elements [16], its activation by NF-B-inducing stimuli is relatively slow [10]. ET-1 mRNA has been found to increase during reperfusion of ischemic porcine hearts [17]. In contrast, a reduction of ET-1 mRNA was found in the present study. This does not exclude an induction of ET-1 at a later phase of reperfusion. The reduction might be related to the increased eNOS, because ET-1 expression is inhibited by NO [18]. ET-1 mRNA may have a biphasic response after ischemia-reperfusion.
Gene expression of inflammatory mediators tended to be higher in patients with unstable angina before cardioplegia, and the patients were more reactive to cardioplegia and reperfusion. This may imply that the intermittent ischemia and reperfusion of unstable angina induced myocardial ischemia before surgery. Clinical, indirect evidence of intermittent myocardial ischemia in unstable angina analogous to ischemic preconditioning is provided by findings that unstable angina before acute myocardial infarction reduces morbidity and mortality compared with patients with acute infarction of sudden onset [19]. Paradoxically, some patients with unstable angina have increased morbidity and mortality during CABG, with pump failure as an important feature [20]. We hypothesized that unstable angina induces a myocardial proinflammatory state, triggering both protective and detrimental substances analogous to ischemic preconditioning. Whether these factors induce a preconditioning-like effect or not may depend on the time frame from start of symptoms to the ischemic/cardioplegic insult.
It is well known that inflammatory and vasoactive substances are released from the heart in ischemia-reperfusion injury [1, 2]. We have demonstrated for the first time the initial steps of gene expression of leukocyte adhesion molecules, proinflammatory cytokines, and vasoactive mediators in the human heart during open heart surgery. Gene expression of inflammatory mediators was most evident in patients with unstable angina, who also expressed eNOS. Nuclear translocation of NFB could explain the activation of the gene program. The increased gene expression was found shortly after hypothermic arrest; more profound effects would be expected hours and days after the incident. Increased knowledge of human myocardial inflammation may lead to development of new therapeutic strategies and improved myocardial repair.
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Acknowledgments |
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ke Wiberg, Harald o Greta Jeanssons, Sigurd and Elsa Goljes Memory, and the Karolinska Institute (all Stockholm, Sweden), and the Family Elquists’ Memory, Nybro, Sweden. |
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