© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Cardiotrophin-1 protects the human myocardium from ischemic injury
Comparison with the first and second window of protection by ischemic preconditioning
aDivision of Cardiac Surgery, Department of Surgery, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK
bDepartment of Medicine and Therapeutics, University of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK
* Corresponding author. Fax: +44-116-232-1282 sudip.ghosh{at}glenfield-tr.trent.nhs.uk
Received 6 March 2000; accepted 24 July 2000
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Background: There are reports suggesting that cardiotrophin 1 (CT-1) is cytoprotective. We investigated the cardioprotective effects of CT-1 on the human myocardium and compared this benefit with the early and delayed protection afforded by ischemic preconditioning (PC). Methods: Right atrium specimens were prepared and incubated in buffer solution at 37°C for 30 min stabilisation, before entering one of the three following studies. In study 1, muscles (n = 6/group) were allocated to one of four groups: (i) aerobic control — incubated in oxygenated media for 210 min, (ii) ischemia alone — 90 min ischemia followed by 120 min reoxygenation, (iii) PC by 5 min ischemia–5 min reoxygenation before 90 min ischemia–120 min reoxygenation and (iv) CT-1 (1 nM) — 90 min ischemia–120 min reoxygenation with exposure to CT-1 throughout the protocol. In study 2, muscles (n = 6/group) were allocated to one of four protocols as in study 1with the exception that were incubated for 24 h followed by 30 or 90 min ischemia–120 min reoxygenation on day 2. In study 3, the same groups were employed as in study 2 with the exception that only a 30-min period of ischemia was used and that CT-1 antibody (5 µg/ml) was added to all groups throughout the experimental protocol. Creatine kinase (CK, U/g wet wt.) leakage into the medium and MTT reduction (OD/mg wet wt.), an index of cell viability, were assessed at the end of the experiment. Results: In study 1, a first window of cardioprotection was observed with PC (CK=4.39±0.34; MTT=0.58±0.03 vs. CK=7.11±0.4;MTT=0.32±0.02 in the ischemic alone group; P<0.001) but not with CT-1(CK=6.65±0.67; MTT=0.31±0.03, P = NS vs. ischemia alone). In study 2, PC applied on day 1 was protective against 30-min ischemia (CK=3.28±0.43; MTT=0.68±0.046, P<0.001 vs. ischemia alone) but not against 90-min ischemia (CK=7.13±0.66; MTT=0.24±0.03, P = NS vs. ischemia alone) induced on day 2 (second window). However, when the tissue was exposed to CT-1 for 24 h, protection was similar to that of PC when subjected to 30 min of ischemia (CK=2.95±0.71; MTT=0.77±0.05, P = NS vs. PC) and greater than PC when subjected to 90 min of ischemia (CK=4.56±0.51; MTT=0.39±0.03, P = 0.002 vs. PC). In study 3, the CT-1 antibody did not affect the protection induced by PC (CK=3.36±0.6; MTT=0.69±0.06) but it abolished the protection obtained with CT-1(CK=5.15±0.81; MTT=0.42±0.06, P = NS vs. ischemia alone group). Conclusions: CT-1 exhibits a significant protection of the human myocardium against ischemic injury when tissue is exposed to this factor for a long period (e.g. 24 h) but not when exposed for a short period (e.g. 2 h). In addition, the protection afforded by long exposure to CT-1 is as potent or even greater than the one obtained by the second window of PC. The protection induced by CT-1 but not that induced by PC can be abolished by CT-1 antibody suggesting that their beneficial action is attained by different mechanisms.
KEYWORDS Hypoxia/anoxia; Preconditioning
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Cardiotrophin-1 (CT-1) is a member of a family of cytokines, which include interleukin-6 (IL-6), and leukaemia inhibitory factor (LIF) [1]. The receptors for each of these factors contain a cell surface polypeptide known as glycoprotein 130 (gp130) [2]. CT-1 and LIF share a common second receptor component known as LIF receptor sub-unit β [2]. In addition, CT-1 interacts with a third receptor component with a molecular weight of 80 kDa [3].
CT-1 is a cardiac myocyte hypertrophy-inducing factor, adding sarcomeres in series rather than in parallel [1] and leading to an increased cardiac myocyte cell length. The hypertrophic response of cardiac myocytes to CT-1 is mediated via the Jak/STAT signalling pathway [4]. In addition, CT-1 exhibits cytoprotective properties. Thus, CT-1 has been shown to prevent apoptosis of myocytes via a pathway dependent on activation of a mitogen activated protein kinase (MAPK) [5] and also has been shown to induce heat shock protein (hsp90 and hsp70) accumulation in cultured cardiac cells and to protect them from thermal or ischemic stress [6]. More recently hypoxic stress has been shown to induce CT-1 mRNA expression in cardiac myocytes [7].
Ischemic preconditioning (PC) is another potent intervention that exhibits two phases of protection, an early or first window of protection (
2 h) and a delayed or second window of protection (
24 h). The underlying mechanism of PC has been extensively investigated, however the basis of such cardioprotection is not fully elucidated. The most favoured current hypothesis for the first window of PC suggests that a variety of endogenous ligands such as adenosine, bradykinin, catecholamines and opioids activate receptors linked to protein kinase C (PKC) to initiate an intracellular signal transduction pathway. PKC may activate a tyrosine kinase, which in turn activates MAP or JUN kinases leading finally to phosphorylation of an effector protein, possibly the mitochondrial KATP channel [8,9]. The beneficial effect of PC can be abolished by the use of MAPK inhibitors [10,11], a mechanism of protection that appears to be shared by CT-1 [5]. The mechanism for the second window of protection of PC, that we have already shown to be present in human myocardium [12], also remains elusive. As in the protection induced by CT-1, it has been hypothesised that the delayed protection of PC may be mediated by increased production of heat shock proteins [13].
The aims of the present studies were: (i) to examine the protective effects of CT-1 on the human myocardium, (ii) to compare the efficacy of any CT-1 induced protection with that of PC, and (iii) to investigate whether CT-1 contributes to the beneficial effect of PC. These studies were carried out in an in vitro model of human right atrial myocardium.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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2.1 Experimental preparation
Experiments were performed on myocardial muscle obtained from the right atrial appendage of patients undergoing elective coronary artery surgery or aortic valve replacement. Patients were excluded if they had large atriums, atrial arrhythmias, poor left ventricular function (ejection fractions <30%), right ventricular failure or were taking oral hypoglycaemic agents or having opioid analgesia. Local ethical committee approval was obtained for the harvesting technique. The specimens were collected in oxygenated HEPES buffered solution at 4–5°C and immediately sectioned and prepared for study. Briefly, the appendage was mounted onto a ground glass plate with the epicardial surface faced down and then sliced using surgical skin graft blades (Shwann-Morton, Sheffield, UK) to a thickness of between 300 and 500 µm. The specimen and the slide were always kept moist throughout the procedure. The muscles (weight 30–50 mg) were then transferred to conical flasks (25-ml Erlenmeyer flasks, Duran, Astell Scientific, Kent, UK) containing 10 ml of oxygenated buffered solution. Following this, the flasks were placed in a shaking water bath maintained at 37°C. The oxygenation of the incubation medium was maintained by a continuous flow of 95% O2–5% CO2 gas mixture to obtain a pO2 between 25 and 30 kPa and a pCO2 between 6 and 6.5 kPa. The pO2, pCO2 and pH in the incubation medium were monitored by intermittent analyses of the effluent by using an automated blood gas analyser (model 855 Blood Gas System, Chiron Diagnostics, Cambridge, UK) and the pH was kept between 7.36 and 7.45. For the induction of simulated ischemia, the medium was bubbled with 95% N2–5% CO2 (pH 6.80–7.00) and D-glucose removed (see below). The pO2 in the ischemic medium was 0. In this preparation, tissue injury and viability were assessed (see below) but the atrium was not paced and force development was not measured.
2.2 Solutions
The incubation medium was prepared daily with deionised distilled water and contained (in mM): NaCl (118), KCl (4.8), NaHCO3 (27.2), KH2PO4 (1), MgCl2 (1.2), CaCl2 (1.25), D-glucose (10) and HEPES (20). During simulated ischemia, the substrate D-glucose was removed and replaced with 2-deoxyglucose (10 mM) to maintain a constant osmolarity. All reagents were obtained from Sigma CT-1 was purchased from Chemicon (Harrow, UK).
2.3 Production of CT-1 antibody
Oligopeptides (referred to as CT peptides) corresponding to amino acids 105–120 (CRRQAELNPRAPRLLR) and 186–199 (SRTEGDLGQLLPGG) of the human CT-1 sequence, representing the mid and C-terminal sections of CT-1 were synthesised in the MRC Toxicology Unit, Leicester University and then purified by high-performance liquid chromatography [14]. The CT peptide was conjugated to hemocyanin with 
-maleimidocaproic acid N-hydroxysuccinimide ester as previously described [14]. Two rabbits were inoculated with subcutaneous injections of antigen (1 mg) emulsified with complete Freund's adjuvant with booster injections (0.5 mg) given subcutaneously every 2 weeks. The IgG fractions of the CT antisera were obtained by protein A Sepharose chromatography and specifically bound to the respective peptide sequences against which they were raised. The antibodies showed no cross reactivity to cytokines such as interleukin-6 and leukemia inhibitory factor, or to the natriuretic peptides (ANP, BNP or CNP). A 26-kDa protein was detected, consistent with cardiotrophin-1 on western blots [14].
2.4 Experimental protocols
After sectioning the atrium, the preparations were allowed to stabilise for 30 min and then randomly allocated to various protocols. In all studies simulated ischemia was induced for a period of 30 or 90 min followed by 120 min of reoxygenation.
2.4.1 Study 1
In this study, the early protective effect of CT-1 was investigated and its efficacy compared with the first window of PC. Fig. 1a shows the time course for the four study groups (n = 6/group). In the CT-1 treated group, the cytokine at a concentration of 1 nM was present in the incubation media for 10 min prior to and during the 90-min ischemia period and the 120-min reoxygenation period. PC was induced by a single cycle of 5 min ischemia–5 min reoxygenation. We have shown that this PC protocol provides maximal protection in this model [12].
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2.4.2 Study 2
In this study, the delayed protective of CT-1 was investigated and its efficacy compared with the second window of protection of PC. Fig. 1b shows the experimental time course for all study groups (n = 6/group). We have previously demonstrated in our laboratory [15] that the human right atrial preparation used in the present studies remains viable for at least 24 h but that it is more sensitive to short periods of ischemia (i.e. 30 min ischemia) when these are followed by 24 h of aerobic incubation. For this reason, two periods of ischemia, 30 and 90 min, were studied. In the CT-1 treated group, the cytokine also at a concentration of 1 nM was introduced after the 30-min stabilization period and then it was present in the incubation media through out the entire experimental time. Again PC consisted of a single cycle of 5 min ischemia–5 min reoxygenation.
2.4.3 Study 3
In this study, the possibility that CT-1 may contribute to the second window of protection of PC was investigated. The experimental time course for the study (n = 6/group) was identical to that used in study 2 (Fig. 1b) with the exception that only a 30-min period of ischemia was used and that CT-1 polyclonal IgG antibodies (5 µg/ml) were added to incubation media of all groups after the 30-min stabilization period and for the entire experimental time in order to neutralise the effects of CT-1.
2.5 Assessment of tissue injury and viability
At the end of each experimental protocol, tissue injury was determined by measuring the leakage of creatine kinase (CK) into the incubation medium and tissue viability by the reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) to blue formazan product.
2.5.1 CK leakage
The activity of CK leakage into the media during the reoxygenation period (U/g wet wt) was assayed by a kinetic ultraviolet method based on the formation of NAD (Sigma Cat. No. 1340-K) at 37°C.
2.5.2 MTT reduction
At the end of the experimental time, the tissue was loaded into a Falcon conical tube (15 ml, Becton Dickinson Labware, Cowley, Oxford, UK) and 2 ml of phosphate buffer solution (Na2HPO4, 40 mM; NaH2PO4, 9.6 mM and NaCl, 36 mM; pH 7.40) containing MTT (1.25 mg/ml, 3 mM at final concentration) was added, incubated for 30 min at 37°C and then homogenised in 2 ml dimethylsulfoxide (Homogenizer Ultra-Turrax T25, dispersing tool G8, IKA-Labortechnic, Staufen, Germany) at 9500 rpm for 1 min. The homogenate was then centrifuged at 1000 g for 10 min and 0.2 ml of the supernatant was dispensed into a 98-well flat-bottom microtiter plate (Nunc Brand Products, Roskilde, Denmark). After this, the absorbance was measured on a plate reader (Benchmark, Bio-Rad, Hercules, CA, USA) at 550 nm and the results expressed as OD/mg wet wt.
2.6 Statistical analysis
All data are presented as mean±SEM. All values were compared by ANOVA with application of a post-hoc Tukey's test. A Bonferroni's correction for multiple comparisons was applied where there was border line significance. Statistical significance was assumed at the P<0.05 level.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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All samples entering the studies completed the applied experimental protocol and were included in the analysis.
3.1 Study 1 — early protective effect of CT-1 and comparison of its efficacy with the first window of PC
As shown in Fig. 2a, 90 min of ischemia resulted in significant increase in CK leakage. As expected, PC applied immediately before the 90-min ischemic period (first window) caused a significant reduction in CK leakage. However, CT-1 at a concentration of 1 nM, which has been reported to be above the physiological plasma levels [14], had no significant effect. Fig. 2b shows the results of the MTT reduction that were a mirror image of the results on CK leakage. Thus, ischemia alone resulted in 53% decrease in MTT reduction of the values seen in the aerobic control group, a value that was significantly improved to 22% by PC whereas it was unchanged by CT-1 (54%). A dose –response study for CT-1 at concentrations between 0 and 100 nM showed no significant effect against ischemia-induced increase in CK leakage or decrease in MTT reduction (data not shown).
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, P<0.05 vs. ischemia alone group; ¶ P<0.05 vs. PC group.3.2 Study 2 — delayed protective effect of CT-1 and comparison of its efficacy with the second window of PC
As mentioned earlier, because this preparation is more sensitive to ischemia following 24 h of aerobic incubation, two periods of ischemic times, 30 and 90 min, were investigated. A dose–response study for CT-1 at concentrations between 0 and 1 nM was carried out and revealed that the lowest most effective concentration was 1 nM.
Fig. 3a and b show the results with 30 min ischemia for CK leakage and MTT reduction, respectively. Ischemia alone caused a 274% increase in CK leakage and 41% decrease in MTT reduction when compared with the aerobic control group. As previously observed [12], the second window of PC significantly decreased CK leakage (184% of aerobic control) and improved MTT reduction (80% of aerobic control). Interestingly, now that the period of incubation with CT-1 was extended beyond 24 h, there was a significant decrease in CK leakage (166% of aerobic control)) and increase in MTT reduction (89.5% of aerobic control), a protective effect that was similar to that seen with PC.
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As expected and as shown in Fig. 4a and b, extension of the period of ischemia to 90 min resulted in greater CK leakage and lower MTT reduction than with 30-min ischemia. Severe ischemia resulted in significant necrosis of the myocardial cells with tissue viability reduced to 28% of aerobic controls. The loss of the beneficial effect of PC on both CK leakage and MTT reduction with extension of the ischemic injury was also expected since similar results were previously observed in our laboratory [12]. In contrast, the CT-1 treated group showed a significant decrease in CK leakage (232% of aerobic control) and greater MTT reduction (49% of aerobic control) than the ischemia alone and PC groups. The protection observed in the CT-1 treated group was seen only when the myocardial slices were incubated for a long period (i.e. 24 h) before being subjected to ischemia. Experiments with shorter periods of exposure to CT-1 (i.e. 2 h) on day 1 showed no beneficial effect when ischemia was induced 24 h later (data not shown).
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3.3 Study 3 — role of CT-1 on the second window of PC
To study whether CT-1 may a play a role in the second window of protection of PC, the CT-1 antibody was added to the incubation media for the entire experimental protocol. Preliminary dose–response studies for the CT-1 antibody at concentrations between 0 and 50 µg/ml had shown that the minimal effective concentration for CT-1 antibody which abolished CT-1-induced protection was 5 µg/ml IgG. Fig. 5a and b shows the results of CK leakage and MTT reduction. The presence of the CT-1 antibody in the aerobic control group did not affect the stability of the preparation as suggested by similar CK leakage and MTT reduction mean values as those seen in study 2. Furthermore, CT-1 antibody did not affect the injury sustained during ischemia since both CK leakage and MTT reduction mean values were similar to those seen in study 2. Importantly, the protection observed by CT-1 in study 2 was lost in the presence of the antibody, whereas the beneficial effects of the second window of PC were not affected by the presence of CT-1 antibody, as indicated by the MTT values (49 and 81% of aerobic control, respectively). It should be mentioned that in this study the changes in CK leakage were modest and did not achieve statistical significance.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Ischemic heart syndromes and their complications are the most important causes of deaths in developed countries. As a result, for the last decades significant effort and resources have been directed to understand the pathophysiology of ischemia-induced injury and to investigate the means to counteract this effect. The discovery that the heart possesses potent intrinsic protective mechanisms against ischemic injury such as ischemic preconditioning [16] has created high expectations that protection can be more effectively achieved by manipulating the tissues own defence machinery. At present, there is strong experimental evidence that the protection induced by preconditioning may be mediated by activation of mitochondrial KATP channels [9,17] via PKC activation [18] and participation of the tyrosine kinase and MAP kinase cascades [19] although the exact mechanism and whether the protection may be obtained by additional factors and different pathways remain unclear.
CT-1 is a recently described cytokine that has been suggested to have a number of actions including the hypertrophy of cardiac myocytes in vitro [20] and stimulation of the survival of cultured cardiac myocytes [6,7]. Plasma levels of CT-1 have been shown to be elevated in patients with acute myocardial infarction by us [21] and this has lead to the notion that CT-1 may be involved in an intrinsic mechanism against ischemic injury. The present studies demonstrate for the first time that CT-1 has a powerful protective effect against ischemic injury in the human myocardium. We also have shown that to obtain protection the myocardium has to be exposed to CT-1 for a period longer than 2 h and that the degree of protection may be as potent or even greater than the second window of ischemic preconditioning. Stephanou et al. [6] have recently reported that neonatal rat cardiac myocytes are protected against ischemic injury when incubated with 1 ng/ml of CT-1, a concentration identical to the one used in our studies. The results of our study in the human myocardium support the results of this study in the rodent myocardium.
The mechanism of CT-1 induced cardiac protection is unknown. It has been reported that activation of the p42/p44 MAP kinase pathway is necessary for the increased survival of cardiac myocytes by CT-1 [22] and that the cardioprotective effect of CT-1 is associated to an increased production of heat shock proteins [6]. Similar mechanisms have also been described as an explanation for the protection induced by ischemic preconditioning [13,18,19]. However, the present studies have shown that the beneficial effect of CT-1 is probably mediated by a mechanism different from that of preconditioning. Thus, CT-1 required a long exposure period to induce protection which distinctly compares with the readily obtainable first window of protection of preconditioning. Furthermore, the protection afforded by CT-1 was as potent or even greater than that of preconditioning and whereas CT-1 antibody abolished CT-1-induced protection, it did not influence the beneficial effect of preconditioning. Certainly, further research is warranted to elucidate the mechanism of protection of CT-1.
The novel cardioprotection of CT-1 may have important clinical implications. The exogenous administration of CT-1 may be useful to prevent or reduce injury in the course of imminent acute ischemic syndromes and in the context of coronary angioplasty and cardiac surgery and transplantation. A potential therapeutical alternative may be the stimulation of the production of CT-1 by the parient's own body. The definition of these treatment modalities is an area that also needs further investigation.
There are several potential limitations, which should be acknowledged in this study. First, right atrial appendages were obtained from patients subjected to various medical treatments (e.g. nitrates, β-blockers, calcium antagonists) and that in principle may have influenced ischemia–reperfusion injury and protection by the study interventions. However, it should be emphasised that all medication was stopped the day before surgery when specimens were taken for the study and that significant effect of the medication was unlikely since all preparations responded to ischemia–reperfusion with a similar degree of injury and the effects of preconditioning and CT-1 treatment were uniform in all instances when applied. Second, it should be mentioned that the preparation used in this study was not electrically stimulated (i.e. non-beating) and therefore one should be cautious when extrapolating to the in vivo situation. Third, in experiments in study 3 the cardioprotective effects of exogenously added CT-1 was totally abrogated by co-incubation with the CT-1 specific antibodies. Care was taken to ensure that the myocardial slices were preincubated with the antibodies to ensure tissue penetration before any experimental procedures. It seems unlikely that endogenously produced CT-1 could be secreted and act locally at the gp130/LIF receptors in very high concentrations, since the high concentration of exogenously added CT-1 (1 nM) was completely neutralised by the polyclonal antibodies (5 µg/ml) which were present in excess. However, we cannot be certain that endogenous CT-1 could be secreted into a compartment to which the neutralising antibodies had poor access.
In conclusion, we have demonstrated that CT-1 has a protective effect against ischemia in human adult myocardium. This protection is only afforded when tissue is exposed to this factor for a long period (e.g. 24 h) but not when exposed for a short period (e.g. 2 h). In addition, the protection afforded by long exposure to CT-1 is as potent or even greater than the obtained by the second window of PC. The protection induced by CT-1 but not that induced by PC can be abolished by CT-1 antibody suggesting that their beneficial action is attained by different mechanisms.
Time for primary review 24 days.
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Z. Liao, B. K. Brar, Q. Cai, A. Stephanou, R. M. O'Leary, D. Pennica, D. M. Yellon, and D. S. Latchman Cardiotrophin-1 (CT-1) can protect the adult heart from injury when added both prior to ischaemia and at reperfusion Cardiovasc Res, March 1, 2002; 53(4): 902 - 910. [Abstract] [Full Text] [PDF]
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 T. Tsuruda, M. Jougasaki, G. Boerrigter, B. K. Huntley, H. H. Chen, A. B. D'Assoro, S. C. Lee, A. M. Larsen, A. Cataliotti, and J. C. Burnett Jr Cardiotrophin-1 Stimulation of Cardiac Fibroblast Growth: Roles for Glycoprotein 130/Leukemia Inhibitory Factor Receptor and the Endothelin Type A Receptor Circ. Res., February 8, 2002; 90(2): 128 - 134. [Abstract] [Full Text] [PDF]
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 C. R Holleyman and D. F Larson Apoptosis in the ischemic reperfused myocardium Perfusion, December 1, 2001; 16(6): 491 - 502. [Abstract] [PDF]
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T. Tsuruda, M. Jougasaki, G. Boerrigter, B. K. Huntley, H. H. Chen, A. B. D'Assoro, S. C. Lee, A. M. Larsen, A. Cataliotti, and J. C. Burnett Jr Cardiotrophin-1 Stimulation of Cardiac Fibroblast Growth: Roles for Glycoprotein 130/Leukemia Inhibitory Factor Receptor and the Endothelin Type A Receptor Circ. Res., February 8, 2002; 90(2): 128 - 134. [Abstract] [Full Text] [PDF]
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