222
Letters to the Editor
[10] Ferraris VA, Brown JR, Despotis GJ, et al. Society of Thoracic Surgeons Blood Conservation Guideline Task Force. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91:944–82.
[11] Dixon B, Santamaria JD, Reid D, et al. The association of blood transfusion with mortality after cardiac surgery: cause or confounding? Transfusion 2013;53:19–27. [12] Mehta RH, Sheng S, O'Brien SM, et al. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: incidence, risk factors, time trends, and outcomes. Circ Cardiovasc Qual Outcomes 2009;2:583–90.
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.199
Letter in response to “Acute Coronary Involvement in Acute Type A Aortic Dissection: A Subgroup Analysis of Bicuspid Aortic Valve and Marfan Syndrome”☆ Tsu-Ming Chien a,b, Chih-Wei Chen c, Cai-Pei Yu d, Huai-Min Chen e,f, Ying-Fu Chen e,f,⁎ a
Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan d Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan e Division of Cardiovascular Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan f Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan b c
a r t i c l e
i n f o
Article history: Received 12 November 2013 Accepted 28 December 2013 Available online 7 January 2014 Keywords: Acute aortic dissection Acute coronary involvement Bicuspid aortic valve Marfan syndrome Coronary malperfusion
The letter by Dr. Wang et al. [1] addresses several important issues regarding acute coronary involvement in acute type A aortic dissection. First of all, we would like to thank their critical and insightful comments on our article [2]. Dr. Wang et al. shared a similar experience in regard to the incidence of acute coronary involvement (ACI) (14.6%, 56/384, vs. 14.1%, 20/142) and a comparable in-hospital mortality rate (17.9%, 10/56 vs. 20%, 4/20) in this special patient group as compared with our cohort study. Secondly, Dr. Wang et al. have pointed out that ACI cases associated with ostial damage (type A and type B) presented with a higher inhospital mortality than that of the cases without ostial damage (type C and type D) (22.6% vs. 12.0%, p = 0.485). This is in line with the observation that we have (27.3% vs. 11.1%, p = 0.369). As already mentioned in the study limitations of our article [2], we acknowledge the fact that the small sample size impacts the statistical power of our study. Therefore, further prospective multicenter studies are needed to identify whether the above-mentioned confounding variable may have an impact on in-hospital mortality. Nevertheless, the similar trend observed by Dr. Wang et al. implicates that patients with ostial damage might be potential to have a higher in-hospital mortality than that of patients without ostial damage. Contemporary reports of in-hospital mortality after surgical repair of acute aortic dissection type A (AADTA) ☆ Funding: This work was partially supported by a grant from the National Science of Council of Taiwan (NSC) (102-2314-B037-027). ⁎ Corresponding author at: Division of Cardiovascular Surgery Department of Surgery, Kaohsiung Medical University Hospital, 100, Shih-Chuan 1st Rd, Kaohsiung, Taiwan. Tel.: + 886 7 3121101x5801 3; fax: +886 7 3127056. E-mail address: [email protected] (Y.-F. Chen).
has ranged from 10% to 25%. AADTA associated ACI still carries a higher mortality, especially concomitant with coronary malperfusion. In the presence of coronary malperfusion, in-hospital mortality doubles and some patients will die intraoperatively from low cardiac output syndrome [3]. As pointed by Dr. Wang et al., more frequently to have coronary ostial damage and more evidence of preoperative myoischemia in patients with BAV or MFS of their ACI patient cohort. Therefore, we concur with Dr. Wang et al.'s comment that, “…both preoperative myocardial ischemia and operational inconvenience during restoration of myocardial perfusion and aortic root replacement procedures brought up by the structural damage in coronary artery ostial region could increase perioperative hazards” [1]. Thirdly, it is important to note that Dr. Wang et al. addresses that the in-hospital mortality was higher in ACI patients with congenital bicuspid aortic valve (BAV) and Marfan syndrome (MFS) compared to that of ACI patients associated with tricuspid aortic valve (TAV). The reason why ACI patients associated with BAV or MFS disclosed a higher in-hospital mortality is still not fully understood, but Dr. Wang et al. indicated that coronary ostial damage was more frequently present in BAV and MFS groups compared to that of TAV group. In addition, congenital coronary anomalies have been variably described in association with BAV [4,5] and MFS [6]. A predilection (24–57%) towards left coronary artery dominance and a shorter length of left main coronary artery have been demonstrated in BAV subjects [4,7]. Thus, the increased incidence of coronary abnormalities and more frequently to have coronary ostial damage may have clinical relevance with regard to the clinical challenge on aortic root replacement, coronary artery bypass grafting and cardioplegia procedures during aortic dissection repair [1,8,9]. Therefore, we also agree with Dr. Wang et al.'s comment that predisposing dissection-associated diseases (namely BAV and MFS) and their characteristics of ACI classification traits might deeply influence surgical options and present as important prognostic factors in patients undergoing repair for acute type A aortic dissection with ACI. The only concern is the small sample size of BAV (n = 5) and MFS (n = 9) patients enrolled in their study. Lastly, as mentioned, we agree with the suggestion by Dr. Wang et al. [1]. In ACI patients with BAV or MFS, further evaluation for their intrinsic aortic valve pathology [10] and coronary anatomic variants and individualized problem-solving surgical strategy should be contemplated in order to improve the hospital outcomes of this
Letters to the Editor
specific cohort. We thank Dr. Wang et al. for providing their valuable experience and sharing it with us. We also appreciate their suggestions and constructive comments. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
References [1] Wang Y, Wu B, Dong L, Wang C, Shu X. Acute coronary involvement in acute type A aortic dissection: a subtype analysis of bicuspid aortic valve and Marfan syndrome. Int J Cardiol 2013 [Manuscript No.: IJC-D-13-03341]. [2] Chen YF, Chien TM, Yu CP, et al. Acute aortic dissection type A with acute coronary involvement: a novel classification. Int J Cardiol 2013;168:4063–9.
223
[3] Bonser RS, Ranasinghe AM, Loubani M, et al. Evidence, lack of evidence, controversy, and debate in the provision and performance of the surgery of acute type A aortic dissection. J Am Coll Cardiol 2011;58:2455–74. [4] Braverman AC, Guven H, Beardslee MA, Maken M, Kates AM, Moon MR. The bicuspid aortic valve. Curr Probl Cardiol 2005;30:470–522. [5] Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am Coll Cardiol 2010;55:2789–800. [6] Brother JA, Harris MA, Paridon SM. Anomalous aortic origin of a coronary artery in siblings with Marfan syndrome. Cardiol Young 2011;21:238–40. [7] Lerer PK, Edwards WD. Coronary arterial anatomy in bicuspid aortic valve. Necropsy study of 100 hearts. Br Heart J 1981;45:142–7. [8] Chien TM, Chen CW, Chen HM, Lee CS, Lin CC, Chen YF. Double right coronary artery and its clinical implications. Cardiol Young Mar 5 2013:1–8. [9] Hechadi J, Kerchove LD, Tamer S, El Khoury G. Modified valve-sparing reimplantation technique for paracommissural coronary ostia. Eur J Cardiothorac Surg September 19 2013 [Epub ahead of print]. [10] Aydin A, Desai N, Bernhardt AMJ, et al. Ascending aortic aneurysm and aortic valve dysfunction in bicuspid aortic valve disease. Int J Cardiol 2013;164:301–5.
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.198
Nrf-2–HO-1–HMGB1 axis: An important therapeutic approach for protection against myocardial ischemia and reperfusion injury Jichun Wang, Xiaorong Hu, H. Jiang ⁎ Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuchang, 430060 Wuhan, PR China
a r t i c l e
i n f o
Article history: Received 16 November 2013 Accepted 29 December 2013 Available online 11 January 2014 Keywords: Myocardial ischemia and reperfusion Nrf-2 Heme oxygenase-1 Cardioprotection Oxidative stress
Myocardial reperfusion therapy is the optimal therapeutic strategy for acute myocardial infarction to preserve myocardial viability and function by reversing myocardial ischemia and reducing the infarct size [1]. However, the subsequent ischemia and reperfusion (I/R) injury may attenuate the therapeutic benefit [1]. Although reperfusion therapy is essential for the survival of ischemic tissue, reperfusion itself may cause additional cellular injury by causing local myocardial inflammation, accompanying with apoptosis, which could result in myocardial cell damage [2]. High mobility group box 1 protein (HMGB1), a highly conserved nuclear protein that could regulate gene transcription and maintain the nucleosome structure could be passively released from necrotic cell, apoptotic cell or actively secreted by innate immune cells (such as macrophages and monocytes) [3]. Present study shows that HMGB1 as a novel pro-inflammatory cytokine and contributes to the pathophysiological progress of myocardial I/R injury [4]. HMGB1 may promote the release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and, which could be inhibited by HMGB1 A box peptide (a specific HMGB1 antagonist) and attenuate myocardial I/R injury [4], demonstrating that inhibiting HMGB1 expression could suppress the local myocardial inflammation in myocardial I/R injury. Hence, these suggested that ⁎ Corresponding author. Tel.: +86 27 88041911; fax: +86 27 88040334. E-mail address: [email protected] (H. Jiang).
HMGB1 may become a potential therapeutic target for myocardial I/R injury and anti-HMGB1 over-expression or release could attenuate myocardial I/R injury [5]. Heme oxygenase-1 (HO-1), an inducible isoform of heme oxygenase (HO) enzymes, has been reported to be antiinflammatory, anti-apoptotic, and anti-proliferating in several cell types, including cardiac myocytes [6]. Recently, Liu et al. [7] have further demonstrated that Hydroxysafflor Yellow A could provide a protective effect on I/R injury in H9c2 cardiomyocytes by upregulating the expression and activity of HO-1, which indicate that HO-1 may play an important protective effect on anoxia/reoxygenation or I/R injury. Additionally, Takamiya et al. [8] have further showed that the circulating levels of HMGB1 have been proven to be higher in HO-1−/− mice than HO-1+/+ mice. Meanwhile, Tsoyi et al. [9] have also indicated that the release of HMGB1 in endotoxin-activated macrophages could be prevented by the HO-1 induction in vitro and septic animals in vivo. Thus, these suggested that the HO-1 induction plays an important role in anti-inflammatory effect and could prevent anoxia/reoxygenation or I/R injury by inhibiting HMGB1 release [10]. Nuclear factor-erythroid 2-related factor 2 (Nrf2), as a nuclear transcription factor, has been proven to be as a critically important mechanism for cellular protection and cell survival [11]. Of note, the cinnamon-derived dietary factor cinnamic aldehyde has been proven to mediate Nrf-2 translocation to activate the Nrf2-dependent antioxidant response in human epithelial colon cells [12]. Importantly, the Nrf-2 translocation has been further demonstrated to regulate antioxidant response by playing an essential role in the induction of HO-1 [13], Furthermore, Ha et al. [14] have proved that isoproterenol could mediate HO-1 induction via Nrf-2 translocation to inhibit the HMGB1 release in LPS-activated RAW 264.7 cells and increases in survival rate of CLP-induced septic mice. In addition, Wang et al. [15] have further demonstrated that dobutamine could also mediate HO1 induction via Nrf-2 translocation to inhibit the HMGB1 release in rat myocardial I/R injury in vivo. In conclusion, these suggested that Nrf-2 translocation could play an important role in the induction of HO-1 and Nrf-2–HO-1–HMGB1 axis regulation may exist in
Letters to the Editor
[10] Ferraris VA, Brown JR, Despotis GJ, et al. Society of Thoracic Surgeons Blood Conservation Guideline Task Force. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91:944–82.
[11] Dixon B, Santamaria JD, Reid D, et al. The association of blood transfusion with mortality after cardiac surgery: cause or confounding? Transfusion 2013;53:19–27. [12] Mehta RH, Sheng S, O'Brien SM, et al. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: incidence, risk factors, time trends, and outcomes. Circ Cardiovasc Qual Outcomes 2009;2:583–90.
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.199
Letter in response to “Acute Coronary Involvement in Acute Type A Aortic Dissection: A Subgroup Analysis of Bicuspid Aortic Valve and Marfan Syndrome”☆ Tsu-Ming Chien a,b, Chih-Wei Chen c, Cai-Pei Yu d, Huai-Min Chen e,f, Ying-Fu Chen e,f,⁎ a
Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan d Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan e Division of Cardiovascular Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan f Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan b c
a r t i c l e
i n f o
Article history: Received 12 November 2013 Accepted 28 December 2013 Available online 7 January 2014 Keywords: Acute aortic dissection Acute coronary involvement Bicuspid aortic valve Marfan syndrome Coronary malperfusion
The letter by Dr. Wang et al. [1] addresses several important issues regarding acute coronary involvement in acute type A aortic dissection. First of all, we would like to thank their critical and insightful comments on our article [2]. Dr. Wang et al. shared a similar experience in regard to the incidence of acute coronary involvement (ACI) (14.6%, 56/384, vs. 14.1%, 20/142) and a comparable in-hospital mortality rate (17.9%, 10/56 vs. 20%, 4/20) in this special patient group as compared with our cohort study. Secondly, Dr. Wang et al. have pointed out that ACI cases associated with ostial damage (type A and type B) presented with a higher inhospital mortality than that of the cases without ostial damage (type C and type D) (22.6% vs. 12.0%, p = 0.485). This is in line with the observation that we have (27.3% vs. 11.1%, p = 0.369). As already mentioned in the study limitations of our article [2], we acknowledge the fact that the small sample size impacts the statistical power of our study. Therefore, further prospective multicenter studies are needed to identify whether the above-mentioned confounding variable may have an impact on in-hospital mortality. Nevertheless, the similar trend observed by Dr. Wang et al. implicates that patients with ostial damage might be potential to have a higher in-hospital mortality than that of patients without ostial damage. Contemporary reports of in-hospital mortality after surgical repair of acute aortic dissection type A (AADTA) ☆ Funding: This work was partially supported by a grant from the National Science of Council of Taiwan (NSC) (102-2314-B037-027). ⁎ Corresponding author at: Division of Cardiovascular Surgery Department of Surgery, Kaohsiung Medical University Hospital, 100, Shih-Chuan 1st Rd, Kaohsiung, Taiwan. Tel.: + 886 7 3121101x5801 3; fax: +886 7 3127056. E-mail address: [email protected] (Y.-F. Chen).
has ranged from 10% to 25%. AADTA associated ACI still carries a higher mortality, especially concomitant with coronary malperfusion. In the presence of coronary malperfusion, in-hospital mortality doubles and some patients will die intraoperatively from low cardiac output syndrome [3]. As pointed by Dr. Wang et al., more frequently to have coronary ostial damage and more evidence of preoperative myoischemia in patients with BAV or MFS of their ACI patient cohort. Therefore, we concur with Dr. Wang et al.'s comment that, “…both preoperative myocardial ischemia and operational inconvenience during restoration of myocardial perfusion and aortic root replacement procedures brought up by the structural damage in coronary artery ostial region could increase perioperative hazards” [1]. Thirdly, it is important to note that Dr. Wang et al. addresses that the in-hospital mortality was higher in ACI patients with congenital bicuspid aortic valve (BAV) and Marfan syndrome (MFS) compared to that of ACI patients associated with tricuspid aortic valve (TAV). The reason why ACI patients associated with BAV or MFS disclosed a higher in-hospital mortality is still not fully understood, but Dr. Wang et al. indicated that coronary ostial damage was more frequently present in BAV and MFS groups compared to that of TAV group. In addition, congenital coronary anomalies have been variably described in association with BAV [4,5] and MFS [6]. A predilection (24–57%) towards left coronary artery dominance and a shorter length of left main coronary artery have been demonstrated in BAV subjects [4,7]. Thus, the increased incidence of coronary abnormalities and more frequently to have coronary ostial damage may have clinical relevance with regard to the clinical challenge on aortic root replacement, coronary artery bypass grafting and cardioplegia procedures during aortic dissection repair [1,8,9]. Therefore, we also agree with Dr. Wang et al.'s comment that predisposing dissection-associated diseases (namely BAV and MFS) and their characteristics of ACI classification traits might deeply influence surgical options and present as important prognostic factors in patients undergoing repair for acute type A aortic dissection with ACI. The only concern is the small sample size of BAV (n = 5) and MFS (n = 9) patients enrolled in their study. Lastly, as mentioned, we agree with the suggestion by Dr. Wang et al. [1]. In ACI patients with BAV or MFS, further evaluation for their intrinsic aortic valve pathology [10] and coronary anatomic variants and individualized problem-solving surgical strategy should be contemplated in order to improve the hospital outcomes of this
Letters to the Editor
specific cohort. We thank Dr. Wang et al. for providing their valuable experience and sharing it with us. We also appreciate their suggestions and constructive comments. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
References [1] Wang Y, Wu B, Dong L, Wang C, Shu X. Acute coronary involvement in acute type A aortic dissection: a subtype analysis of bicuspid aortic valve and Marfan syndrome. Int J Cardiol 2013 [Manuscript No.: IJC-D-13-03341]. [2] Chen YF, Chien TM, Yu CP, et al. Acute aortic dissection type A with acute coronary involvement: a novel classification. Int J Cardiol 2013;168:4063–9.
223
[3] Bonser RS, Ranasinghe AM, Loubani M, et al. Evidence, lack of evidence, controversy, and debate in the provision and performance of the surgery of acute type A aortic dissection. J Am Coll Cardiol 2011;58:2455–74. [4] Braverman AC, Guven H, Beardslee MA, Maken M, Kates AM, Moon MR. The bicuspid aortic valve. Curr Probl Cardiol 2005;30:470–522. [5] Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am Coll Cardiol 2010;55:2789–800. [6] Brother JA, Harris MA, Paridon SM. Anomalous aortic origin of a coronary artery in siblings with Marfan syndrome. Cardiol Young 2011;21:238–40. [7] Lerer PK, Edwards WD. Coronary arterial anatomy in bicuspid aortic valve. Necropsy study of 100 hearts. Br Heart J 1981;45:142–7. [8] Chien TM, Chen CW, Chen HM, Lee CS, Lin CC, Chen YF. Double right coronary artery and its clinical implications. Cardiol Young Mar 5 2013:1–8. [9] Hechadi J, Kerchove LD, Tamer S, El Khoury G. Modified valve-sparing reimplantation technique for paracommissural coronary ostia. Eur J Cardiothorac Surg September 19 2013 [Epub ahead of print]. [10] Aydin A, Desai N, Bernhardt AMJ, et al. Ascending aortic aneurysm and aortic valve dysfunction in bicuspid aortic valve disease. Int J Cardiol 2013;164:301–5.
0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.198
Nrf-2–HO-1–HMGB1 axis: An important therapeutic approach for protection against myocardial ischemia and reperfusion injury Jichun Wang, Xiaorong Hu, H. Jiang ⁎ Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuchang, 430060 Wuhan, PR China
a r t i c l e
i n f o
Article history: Received 16 November 2013 Accepted 29 December 2013 Available online 11 January 2014 Keywords: Myocardial ischemia and reperfusion Nrf-2 Heme oxygenase-1 Cardioprotection Oxidative stress
Myocardial reperfusion therapy is the optimal therapeutic strategy for acute myocardial infarction to preserve myocardial viability and function by reversing myocardial ischemia and reducing the infarct size [1]. However, the subsequent ischemia and reperfusion (I/R) injury may attenuate the therapeutic benefit [1]. Although reperfusion therapy is essential for the survival of ischemic tissue, reperfusion itself may cause additional cellular injury by causing local myocardial inflammation, accompanying with apoptosis, which could result in myocardial cell damage [2]. High mobility group box 1 protein (HMGB1), a highly conserved nuclear protein that could regulate gene transcription and maintain the nucleosome structure could be passively released from necrotic cell, apoptotic cell or actively secreted by innate immune cells (such as macrophages and monocytes) [3]. Present study shows that HMGB1 as a novel pro-inflammatory cytokine and contributes to the pathophysiological progress of myocardial I/R injury [4]. HMGB1 may promote the release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and, which could be inhibited by HMGB1 A box peptide (a specific HMGB1 antagonist) and attenuate myocardial I/R injury [4], demonstrating that inhibiting HMGB1 expression could suppress the local myocardial inflammation in myocardial I/R injury. Hence, these suggested that ⁎ Corresponding author. Tel.: +86 27 88041911; fax: +86 27 88040334. E-mail address: [email protected] (H. Jiang).
HMGB1 may become a potential therapeutic target for myocardial I/R injury and anti-HMGB1 over-expression or release could attenuate myocardial I/R injury [5]. Heme oxygenase-1 (HO-1), an inducible isoform of heme oxygenase (HO) enzymes, has been reported to be antiinflammatory, anti-apoptotic, and anti-proliferating in several cell types, including cardiac myocytes [6]. Recently, Liu et al. [7] have further demonstrated that Hydroxysafflor Yellow A could provide a protective effect on I/R injury in H9c2 cardiomyocytes by upregulating the expression and activity of HO-1, which indicate that HO-1 may play an important protective effect on anoxia/reoxygenation or I/R injury. Additionally, Takamiya et al. [8] have further showed that the circulating levels of HMGB1 have been proven to be higher in HO-1−/− mice than HO-1+/+ mice. Meanwhile, Tsoyi et al. [9] have also indicated that the release of HMGB1 in endotoxin-activated macrophages could be prevented by the HO-1 induction in vitro and septic animals in vivo. Thus, these suggested that the HO-1 induction plays an important role in anti-inflammatory effect and could prevent anoxia/reoxygenation or I/R injury by inhibiting HMGB1 release [10]. Nuclear factor-erythroid 2-related factor 2 (Nrf2), as a nuclear transcription factor, has been proven to be as a critically important mechanism for cellular protection and cell survival [11]. Of note, the cinnamon-derived dietary factor cinnamic aldehyde has been proven to mediate Nrf-2 translocation to activate the Nrf2-dependent antioxidant response in human epithelial colon cells [12]. Importantly, the Nrf-2 translocation has been further demonstrated to regulate antioxidant response by playing an essential role in the induction of HO-1 [13], Furthermore, Ha et al. [14] have proved that isoproterenol could mediate HO-1 induction via Nrf-2 translocation to inhibit the HMGB1 release in LPS-activated RAW 264.7 cells and increases in survival rate of CLP-induced septic mice. In addition, Wang et al. [15] have further demonstrated that dobutamine could also mediate HO1 induction via Nrf-2 translocation to inhibit the HMGB1 release in rat myocardial I/R injury in vivo. In conclusion, these suggested that Nrf-2 translocation could play an important role in the induction of HO-1 and Nrf-2–HO-1–HMGB1 axis regulation may exist in
