Critical role of RAGE and HMGB1 in inflammatory heart disease
Critical role of RAGE and HMGB1 in inflammatory heart disease
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DOI：
10.1073/pnas.1522288113
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发表时间：
2016-01-12
影响因子：
11.1
通讯作者：
Kaya, Ziya
中科院分区：
文献类型：
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作者：
Bangert, Anna;Andrassy, Martin;Kaya, Ziya
对心肌肌钙蛋白I（TnI）的自身免疫应答诱导心肌中的炎症和纤维化。高迁移率族蛋白1（HMGB 1）是一种多功能蛋白质，主要通过与晚期糖基化终产物受体（receptor for advanced glycation end products，RECEPTOR）结合发挥促炎活性。HMGB 1-β轴在炎症性心肌病发病机制中的作用尚未完全清楚。使用良好的TnI诱导的实验性自身免疫性心肌炎（EAM）模型，我们证明了局部和全身HMGB 1蛋白表达升高野生型（WT）小鼠TnI免疫后。此外，使用HMGB 1或抗HMGB 1抗体的HMGB 1的药理学抑制减少了TnI免疫的野生型小鼠的心脏中的炎症。此外，用TnI免疫的RAGE-ko小鼠未显示心脏损伤的结构或生理体征。此外，使用腺相关病毒（AAV）载体的HMGB 1的心脏过表达在wt和RAGE-ko小鼠的心脏中诱导炎症。最后，心肌炎患者显示局部和全身HMGB 1和可溶性β-内酰胺酶（sNAB）表达增加。总之，我们的研究强调了HMGB 1及其主要受体β 1似乎是TnI诱导的EAM发病机制中的关键因素，因为HMGB 1的抑制和β 1的消融抑制了心脏中的炎症。此外，HMGB 1的促炎作用不一定仅依赖于TNF α。HMGB 1的其他受体如Toll样受体（TLR）也可能参与疾病的发病机制。这些发现可以通过HMGB 1和sodium的临床相关性来证实。因此，阻断这些分子之一可能是治疗自身免疫性心肌炎和炎症性心肌病的一种新的治疗策略。
Autoimmune response to cardiac troponin I (TnI) induces inflammation and fibrosis in the myocardium. High-mobility group box 1 (HMGB1) is a multifunctional protein that exerts proinflammatory activity by mainly binding to receptor for advanced glycation end products (RAGE). The involvement of the HMGB1-RAGE axis in the pathogenesis of inflammatory cardiomyopathy is yet not fully understood. Using the well-established model of TnI-induced experimental autoimmune myocarditis (EAM), we demonstrated that both local and systemic HMGB1 protein expression was elevated in wild-type (wt) mice after TnI immunization. Additionally, pharmacological inhibition of HMGB1 using glycyrrhizin or anti-HMGB1 antibody reduced inflammation in hearts of TnI-immunized wt mice. Furthermore, RAGE knockout (RAGE-ko) mice immunized with TnI showed no structural or physiological signs of cardiac impairment. Moreover, cardiac overexpression of HMGB1 using adeno-associated virus (AAV) vectors induced inflammation in the hearts of both wt and RAGE-ko mice. Finally, patients with myocarditis displayed increased local and systemic HMGB1 and soluble RAGE (sRAGE) expression. Together, our study highlights that HMGB1 and its main receptor, RAGE, appear to be crucial factors in the pathogenesis of TnI-induced EAM, because inhibition of HMGB1 and ablation of RAGE suppressed inflammation in the heart. Moreover, the proinflammatory effect of HMGB1 is not necessarily dependent on RAGE only. Other receptors of HMGB1 such as Toll-like receptors (TLRs) may also be involved in disease pathogenesis. These findings could be confirmed by the clinical relevance of HMGB1 and sRAGE. Therefore, blockage of one of these molecules might represent a novel therapeutic strategy in the treatment of autoimmune myocarditis and inflammatory cardiomyopathy.