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Protection of intravenous HMGB1 on myocardial ischemia reperfusion injury
International Journal of Cardiology 184 (2015) 280–282
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Protection of intravenous HMGB1 on myocardial ischemia reperfusion injury De-Yong Zhang a, Ai-Xia Zhang b, Yan-Hong Zhou a, Lan-Hua Wang a, Heng-Chen Yao a,⁎ a b
Department of Cardiology, Liaocheng People's Hospital and Clinical School of Taishan Medical University, Liaocheng 252000, PR China Department of Internal Medcine, Liaocheng Peoples Hospital and Clinical School of Taishan Medical University, Liaocheng 252000, PR China
a r t i c l e
i n f o
Article history: Received 10 January 2015 Accepted 21 February 2015 Available online 24 February 2015 Keywords: High mobility group box 1 Ischemia reperfusion injury Rats
Fifty male Wistar rats (250-300 g) were randomly assigned into 5 groups receiving the following treatment: group 1: sham control (sham) (n = 10): rats treated with surgical manipulation without complete ligation of the left anterior descending coronary artery (LAD). Group 2: ischemia reperfusion group (I/R) (n = 10): rats were treated with complete ligation of LAD for 30 min and reperfusion for 180 min. Group 3: high mobility group box 1 (HMGB) 50 (HMGB1 50 ng/kg, was given intravenously 30 min before ischemia, n = 10). Group 4: HMGB100 (HMGB1 100 ng/kg, was given intravenously 30 min before ischemia, n = 10). Group 5: HMGB200 (HMGB1 200 ng/kg, was given intravenously 30 min before ischemia, n = 10). All the HMGB groups were subjected to myocardial ischemia for 30 min and then reperfusion for 180 min. Serum levels of cardiac tropnin I (cTnI), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured via enzyme linked immunosorbent assay (ELISA). Myocardial levels of malondialdehyde (MDA) and superoxide dismutase (SOD) activities were also determined. Hearts were obtained and myocardial tissue was stained with hematoxylin and eosin (HE). Myocardiocyte and tissue morphology were examined with a digitalized microscope. Data were expressed as means ± SD or percentages where appropriate. SAS 6.12 software was used for statistical processing. One way ANOVA was used to analyze means between groups. P b 0.05 was considered statistically significant. ⁎ Corresponding author. E-mail address: [email protected] (H.-C. Yao).
http://dx.doi.org/10.1016/j.ijcard.2015.02.068 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Serum levels of c-TnI (75.87 ± 7.71 μg/l), TNF-α (69.17 ± 4.56 pg/ml) and IL-6 (398.23 ± 17.15 pg/ml) in I/R group were significantly higher than that in sham group (0.13 ± 0.12 μg/l, 20.88 ± 6.14 pg/ml and 149.39 ± 14.02 pg/ml) (all P b 0.01). Pre-treatment with HMGB1 significantly decreased serum c-TnI, TNF-α and IL-6 than that in the I/R group (P b 0.01 or 0.05). However, as compared with HMGB50 group, the serum levels of c-TnI (69.43 ± 5.17 μg/l vs. 49.36 ± 5.08 μg/l, P b 0.01), TNF-α (58.43 ± 3.57 pg/ml vs 43.64 ± 2.01 pg/ml, P b 0.01) and IL-6 (302.48 ± 24.22 pg/ml vs 219.78 ± 20.53 pg/ml, P b 0.01) in HMGB200 were significantly decreased in an dose dependent manner. Myocardial levels of MDA (9.78 ± 0.34 nmol/mg vs 2.94 ± 0.13 nmol/mg, P b 0.01) in the I/R group were significantly increased while SOD levels (68.91 ± 21.9 μ/mg vs 138.9 ± 29.7, P b 0.01) were significantly decreased as compared with those in the sham group. HMGB1 could prevent the elevation of MDA and decrease of SOD. As compared with the HMGB50 group, MDA (6.92 ± 0.41 nmol/mg vs 3.47 ± 0.25 nmol/mg, P b 0.01) and SOD (87.32 ± 31.6 μ/mg vs 123.89 ± 8.33 μ/mg, P b 0.01) changed significantly in the HMGB200 group. It indicates that intravenous HMGB1 treatment significantly inhibited the increase of the MDA level and the decrease of SOD activities in a dose dependent manner. Myocardial fibers are arranged regularly with clear boundaries and there was no inflammatory infiltration in the sham group (Fig. 1 A). Focal myocardial damage with uneven staining. Morphological changes in affected cardiomyocytes primarily comprised different degrees of swelling, necrosis, myocytolysis, and myofibrillar loss. Myocardial fibers were broken and arranged irregularly. The myocardial infarction foci were infiltrated with a large number of neutrophils in the I/R group (Fig. 1 B). In the HMGB50 groups, myocardial fibers were arranged irregularly. Parts of them were dissolved and broken. The number of myocardiocytes reduced and the intermuscular spaces were widened. Myocardial infarction foci and capillaries are surrounded by infiltration of inflammatory cells (Fig. 1 C). In the HMGB200 group, myocardial fibers were arranged relatively regular. Infiltration of a large number of neutrophils can be found (Fig. 1 E). Acute myocardial infarction (MI) is a primary cause of mortality and morbidity worldwide [1]. When acute MI happens, rapid restore of blood flow by either percutaneous coronary intervention or thrombolytic therapy is the most important strategy for salvaging myocardial tissue from inevitable necrosis. But reperfusion itself can paradoxically result in myocardial injury and profound inflammation response (also called ischemia reperfusion injury) [2]. Pro-inflammation cytokines and infiltration of leukocytes during reperfusion may result in
D.-Y. Zhang et al. / International Journal of Cardiology 184 (2015) 280–282
281
Fig. 1. Histopathological changes of myocardial tissue. (H&E staining, 400×). A: Myocardial morphology in the sham group; B: Myocardial morphology in the I/R group; C: Myocardial morphology in the HMGB50 group; D: Myocardial morphology in the HMGB100 group E: Myocardial morphology in the HMGB200 group.
cardiomyocyte damage. Hence, that, to attenuate myocardial I/R injury, is a very important strategy in the management of acute myocardial ischemia. HMGB1, an ubiquitous and abundant nuclear protein, can either be passively released into the extracellular milieu in response to necrotic signals or actively secreted in response to inflammatory signals [3]. HMGB1 is widely distributed in the liver, brain, spleen, lung, heart, kidney and lymphatic tissue. The first 40 peptide segments of B-box can induce the production of TNF-α and IL-6 [4]. As a pro-inflammation cytokine, HMGB1 takes an important role in many cardiovascular diseases, such as atherosclerosis, myocardial ischemia/reperfusion injuries, heart failure and myocardial infarction [5–9]. Recently, several studies showed that exogenous administration of HMGB1 after myocardial infarction or acute global I/R leads to the recovery of left ventricular function through the regeneration of cardiomyocytes. But once the dose of HMGB1 increased, it can only inhibit inflammation reactions other than improves the recovery of left ventricular function [10–12]. In the present study, we found that intravenous pretreatment with HMGB1 could decrease myocardial I/R injury (c-TnI and myocardial
morphological changes). In addition, intravenous HMGB1 could also decrease serum levels of TNF-α and IL-6 which were important pathophysiological components of myocardial I/R injury, suggesting that HMGB1 could inhibit the inflammation response. Furthermore, HMGB1 could decrease myocardial content of MDA and increase SOD activities, indicating that HMGB1 could inhibit oxidative stress. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. Conflict of interest No conflict of interest to declare. Acknowledgment This work was supported by the Natural Science Fundation of Shandong Province (ZR2013HL017), the Natural Science Foundation of
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D.-Y. Zhang et al. / International Journal of Cardiology 184 (2015) 280–282
Liaocheng City (2012NS13), and the Scientific and Technologic Developing Project of Liaocheng City (2014GJH26). References [1] J.L. Zweiter, M.A. Talukder, The role of oxidants and free radicals in reperfusion injury, Cardiolvasc. Res. 70 (2006) 181–190. [2] H.K. Eltzschig, T. Eckle, Ischemia and reperfusion—from mechanism to translation, Nat. Med. 17 (2011) 1391–1401. [3] S. Oozawa, S. Mori, T. Kanke, H. Takahashi, K.Y. Liu, Effects of HMGB1 on ischemia– reperfusion injury in the rat heart, Circ. J. 72 (2008) 1178–1184. [4] J. Li, R. Kokkola, S. Tabibzadeh, R. Yang, M. Ochani, X. Qiang, H.E. Harris, C.J. Czura, H. Wang, L. Ulloa, H. Wang, H.S. Warren, L.L. Moldawe, M.P. Fink, U. Andersson, K.J. Tracey, H. Yang, Structural basis for the proinflammatory cytokine activity of high mobility group box 1, Mol. Med. 9 (2003) 37–45. [5] T. Kohno, T. Anzai, K. Naito, T. Miyasho, M. Okamoto, H. Yokota, S. Yamada, Y. Maekawa, T. Takahashi, T. Yoshikawa, A. Ishizaka, S. Ogawa, Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling, Cardiovasc. Res. 81 (2009) 565–573.
[6] X.X. Yan, L. Lu, W.H. Peng, L.J. Wang, Q. Zhang, R.Y. Zhang, Q.J. Chen, W.F. Shen, Increased serum hmgb1 level is associated with coronary artery disease in nondiabetic and type 2 diabetic patients, Atherosclerosis 205 (2009) 544–548. [7] A.M. Avalos, K. Kiefer, J. Tian, S. Christensen, M. Shlomchik, A.J. Coyle, A. MarshakRothstein, Rage-independent autoreactive b cell activation in response to chromatin and hmgb1/DNA immune complexes, Autoimmunity 43 (2010) 103–110. [8] H.S. Ding, J. Yang, High mobility group box-1 and cardiovascular diseases, Saudi Med. J. 31 (2010) 486–489. [9] H.C. Yao, A.P. Zhao, Q.F. Han, L. Wu, D.K. Yao, L.X. Wang, Correlation between serum high-mobility group box-1 levels and high-sensitivity C-reactive protein and troponin I in patients with coronary artery disease, Exp. Ther. Med. 6 (2013) 121–124. [10] X. Hu, H. Jiang, B. Cui, C. Xu, Z. Lu, B. He, Preconditioning with high mobility group box 1 protein protects against myocardial ischemia–reperfusion injury, Int. J. Cardiol. 145 (2010) 111–112. [11] F. Biscetti, G. Ghirlanda, A. Flex, Therapeutic potential of high mobility group box-1 in ischemic inury and tissue regeneration, Curr. Vasc. Pharmacol. 9 (2011) 677–681. [12] A.M. Abarbanell, J.A. Hartley, J.L. Herrmann, B.R. Weil, Y. Wang, M.C. Manukyan, J.A. Poynter, D.R. Meldrum, Exogenous high-mobility group box 1 improves myocardial recovery after global ischemia/reperfusion injury, Surgery 149 (2011) 329–335.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Protection of intravenous HMGB1 on myocardial ischemia reperfusion injury De-Yong Zhang a, Ai-Xia Zhang b, Yan-Hong Zhou a, Lan-Hua Wang a, Heng-Chen Yao a,⁎ a b
Department of Cardiology, Liaocheng People's Hospital and Clinical School of Taishan Medical University, Liaocheng 252000, PR China Department of Internal Medcine, Liaocheng Peoples Hospital and Clinical School of Taishan Medical University, Liaocheng 252000, PR China
a r t i c l e
i n f o
Article history: Received 10 January 2015 Accepted 21 February 2015 Available online 24 February 2015 Keywords: High mobility group box 1 Ischemia reperfusion injury Rats
Fifty male Wistar rats (250-300 g) were randomly assigned into 5 groups receiving the following treatment: group 1: sham control (sham) (n = 10): rats treated with surgical manipulation without complete ligation of the left anterior descending coronary artery (LAD). Group 2: ischemia reperfusion group (I/R) (n = 10): rats were treated with complete ligation of LAD for 30 min and reperfusion for 180 min. Group 3: high mobility group box 1 (HMGB) 50 (HMGB1 50 ng/kg, was given intravenously 30 min before ischemia, n = 10). Group 4: HMGB100 (HMGB1 100 ng/kg, was given intravenously 30 min before ischemia, n = 10). Group 5: HMGB200 (HMGB1 200 ng/kg, was given intravenously 30 min before ischemia, n = 10). All the HMGB groups were subjected to myocardial ischemia for 30 min and then reperfusion for 180 min. Serum levels of cardiac tropnin I (cTnI), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured via enzyme linked immunosorbent assay (ELISA). Myocardial levels of malondialdehyde (MDA) and superoxide dismutase (SOD) activities were also determined. Hearts were obtained and myocardial tissue was stained with hematoxylin and eosin (HE). Myocardiocyte and tissue morphology were examined with a digitalized microscope. Data were expressed as means ± SD or percentages where appropriate. SAS 6.12 software was used for statistical processing. One way ANOVA was used to analyze means between groups. P b 0.05 was considered statistically significant. ⁎ Corresponding author. E-mail address: [email protected] (H.-C. Yao).
http://dx.doi.org/10.1016/j.ijcard.2015.02.068 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Serum levels of c-TnI (75.87 ± 7.71 μg/l), TNF-α (69.17 ± 4.56 pg/ml) and IL-6 (398.23 ± 17.15 pg/ml) in I/R group were significantly higher than that in sham group (0.13 ± 0.12 μg/l, 20.88 ± 6.14 pg/ml and 149.39 ± 14.02 pg/ml) (all P b 0.01). Pre-treatment with HMGB1 significantly decreased serum c-TnI, TNF-α and IL-6 than that in the I/R group (P b 0.01 or 0.05). However, as compared with HMGB50 group, the serum levels of c-TnI (69.43 ± 5.17 μg/l vs. 49.36 ± 5.08 μg/l, P b 0.01), TNF-α (58.43 ± 3.57 pg/ml vs 43.64 ± 2.01 pg/ml, P b 0.01) and IL-6 (302.48 ± 24.22 pg/ml vs 219.78 ± 20.53 pg/ml, P b 0.01) in HMGB200 were significantly decreased in an dose dependent manner. Myocardial levels of MDA (9.78 ± 0.34 nmol/mg vs 2.94 ± 0.13 nmol/mg, P b 0.01) in the I/R group were significantly increased while SOD levels (68.91 ± 21.9 μ/mg vs 138.9 ± 29.7, P b 0.01) were significantly decreased as compared with those in the sham group. HMGB1 could prevent the elevation of MDA and decrease of SOD. As compared with the HMGB50 group, MDA (6.92 ± 0.41 nmol/mg vs 3.47 ± 0.25 nmol/mg, P b 0.01) and SOD (87.32 ± 31.6 μ/mg vs 123.89 ± 8.33 μ/mg, P b 0.01) changed significantly in the HMGB200 group. It indicates that intravenous HMGB1 treatment significantly inhibited the increase of the MDA level and the decrease of SOD activities in a dose dependent manner. Myocardial fibers are arranged regularly with clear boundaries and there was no inflammatory infiltration in the sham group (Fig. 1 A). Focal myocardial damage with uneven staining. Morphological changes in affected cardiomyocytes primarily comprised different degrees of swelling, necrosis, myocytolysis, and myofibrillar loss. Myocardial fibers were broken and arranged irregularly. The myocardial infarction foci were infiltrated with a large number of neutrophils in the I/R group (Fig. 1 B). In the HMGB50 groups, myocardial fibers were arranged irregularly. Parts of them were dissolved and broken. The number of myocardiocytes reduced and the intermuscular spaces were widened. Myocardial infarction foci and capillaries are surrounded by infiltration of inflammatory cells (Fig. 1 C). In the HMGB200 group, myocardial fibers were arranged relatively regular. Infiltration of a large number of neutrophils can be found (Fig. 1 E). Acute myocardial infarction (MI) is a primary cause of mortality and morbidity worldwide [1]. When acute MI happens, rapid restore of blood flow by either percutaneous coronary intervention or thrombolytic therapy is the most important strategy for salvaging myocardial tissue from inevitable necrosis. But reperfusion itself can paradoxically result in myocardial injury and profound inflammation response (also called ischemia reperfusion injury) [2]. Pro-inflammation cytokines and infiltration of leukocytes during reperfusion may result in
D.-Y. Zhang et al. / International Journal of Cardiology 184 (2015) 280–282
281
Fig. 1. Histopathological changes of myocardial tissue. (H&E staining, 400×). A: Myocardial morphology in the sham group; B: Myocardial morphology in the I/R group; C: Myocardial morphology in the HMGB50 group; D: Myocardial morphology in the HMGB100 group E: Myocardial morphology in the HMGB200 group.
cardiomyocyte damage. Hence, that, to attenuate myocardial I/R injury, is a very important strategy in the management of acute myocardial ischemia. HMGB1, an ubiquitous and abundant nuclear protein, can either be passively released into the extracellular milieu in response to necrotic signals or actively secreted in response to inflammatory signals [3]. HMGB1 is widely distributed in the liver, brain, spleen, lung, heart, kidney and lymphatic tissue. The first 40 peptide segments of B-box can induce the production of TNF-α and IL-6 [4]. As a pro-inflammation cytokine, HMGB1 takes an important role in many cardiovascular diseases, such as atherosclerosis, myocardial ischemia/reperfusion injuries, heart failure and myocardial infarction [5–9]. Recently, several studies showed that exogenous administration of HMGB1 after myocardial infarction or acute global I/R leads to the recovery of left ventricular function through the regeneration of cardiomyocytes. But once the dose of HMGB1 increased, it can only inhibit inflammation reactions other than improves the recovery of left ventricular function [10–12]. In the present study, we found that intravenous pretreatment with HMGB1 could decrease myocardial I/R injury (c-TnI and myocardial
morphological changes). In addition, intravenous HMGB1 could also decrease serum levels of TNF-α and IL-6 which were important pathophysiological components of myocardial I/R injury, suggesting that HMGB1 could inhibit the inflammation response. Furthermore, HMGB1 could decrease myocardial content of MDA and increase SOD activities, indicating that HMGB1 could inhibit oxidative stress. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. Conflict of interest No conflict of interest to declare. Acknowledgment This work was supported by the Natural Science Fundation of Shandong Province (ZR2013HL017), the Natural Science Foundation of
282
D.-Y. Zhang et al. / International Journal of Cardiology 184 (2015) 280–282
Liaocheng City (2012NS13), and the Scientific and Technologic Developing Project of Liaocheng City (2014GJH26). References [1] J.L. Zweiter, M.A. Talukder, The role of oxidants and free radicals in reperfusion injury, Cardiolvasc. Res. 70 (2006) 181–190. [2] H.K. Eltzschig, T. Eckle, Ischemia and reperfusion—from mechanism to translation, Nat. Med. 17 (2011) 1391–1401. [3] S. Oozawa, S. Mori, T. Kanke, H. Takahashi, K.Y. Liu, Effects of HMGB1 on ischemia– reperfusion injury in the rat heart, Circ. J. 72 (2008) 1178–1184. [4] J. Li, R. Kokkola, S. Tabibzadeh, R. Yang, M. Ochani, X. Qiang, H.E. Harris, C.J. Czura, H. Wang, L. Ulloa, H. Wang, H.S. Warren, L.L. Moldawe, M.P. Fink, U. Andersson, K.J. Tracey, H. Yang, Structural basis for the proinflammatory cytokine activity of high mobility group box 1, Mol. Med. 9 (2003) 37–45. [5] T. Kohno, T. Anzai, K. Naito, T. Miyasho, M. Okamoto, H. Yokota, S. Yamada, Y. Maekawa, T. Takahashi, T. Yoshikawa, A. Ishizaka, S. Ogawa, Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling, Cardiovasc. Res. 81 (2009) 565–573.
[6] X.X. Yan, L. Lu, W.H. Peng, L.J. Wang, Q. Zhang, R.Y. Zhang, Q.J. Chen, W.F. Shen, Increased serum hmgb1 level is associated with coronary artery disease in nondiabetic and type 2 diabetic patients, Atherosclerosis 205 (2009) 544–548. [7] A.M. Avalos, K. Kiefer, J. Tian, S. Christensen, M. Shlomchik, A.J. Coyle, A. MarshakRothstein, Rage-independent autoreactive b cell activation in response to chromatin and hmgb1/DNA immune complexes, Autoimmunity 43 (2010) 103–110. [8] H.S. Ding, J. Yang, High mobility group box-1 and cardiovascular diseases, Saudi Med. J. 31 (2010) 486–489. [9] H.C. Yao, A.P. Zhao, Q.F. Han, L. Wu, D.K. Yao, L.X. Wang, Correlation between serum high-mobility group box-1 levels and high-sensitivity C-reactive protein and troponin I in patients with coronary artery disease, Exp. Ther. Med. 6 (2013) 121–124. [10] X. Hu, H. Jiang, B. Cui, C. Xu, Z. Lu, B. He, Preconditioning with high mobility group box 1 protein protects against myocardial ischemia–reperfusion injury, Int. J. Cardiol. 145 (2010) 111–112. [11] F. Biscetti, G. Ghirlanda, A. Flex, Therapeutic potential of high mobility group box-1 in ischemic inury and tissue regeneration, Curr. Vasc. Pharmacol. 9 (2011) 677–681. [12] A.M. Abarbanell, J.A. Hartley, J.L. Herrmann, B.R. Weil, Y. Wang, M.C. Manukyan, J.A. Poynter, D.R. Meldrum, Exogenous high-mobility group box 1 improves myocardial recovery after global ischemia/reperfusion injury, Surgery 149 (2011) 329–335.