![]() HMGB1 treatment induced cardiac damage and affected activation of inflammation-related genes and signaling cascades in wt and RAGE-ko mice. Maximal decrease in cardiac EF has been seen in wt mice with cardiac overexpression of HMGB1 and additional immunization with TnI.įig. In contrast, Luc-AAV–treated and CFA-immunized mice showed no significant change in cardiac function (wt/HMGB1/CFA: 41.7 ± 9.7% vs. Overexpression of HMGB1 alone without TnI immunization decreased the EF significantly in both wt and RAGE-ko groups. Furthermore, cardiac function of the animals was evaluated ( Fig. In contrast, TnI immunization increased hs-TnT release in Luc-AAV–treated wt but not in RAGE-ko mice. Additional TnI immunization did not increase hs-TnT release any further in HMGB1-treated wt or RAGE-ko mice. 4 A) in both wt and RAGE-ko mice compared with Luc-AAV–treated and CFA-immunized mice (wt/HMGB1/CFA: 448.9 ± 50.5 pg/mL vs. HMGB1 treatment and only CFA immunization generated a significant increase in hs-TnT levels ( Fig. The hs-TnT levels in CFA-immunized mice without AAV9 treatment were <100 pg/mL (detection limit). Specificity of NF-κB binding activity was shown by including a 160-fold molar excess of unlabeled consensus NF-κB oligonucleotide (Cons.). ( G) Electrophoretic mobility shift assay was performed to measure the NF-κB binding activity in myocardium. ( F) Heart tissues were analyzed by Western blot, and fold increase of phosphorylated compared with total STAT3, JAK2, ERK1/2, and JNK proteins was thereby detected. ( E) Myocardial mRNA levels of genes involved in cardiac inflammation. ( D) Representative macroscopic pictures ( Left) and histopathological examinations ( Right) of hearts stained with HE and MT. ( C) Histoscore of inflammation and fibrosis in the hearts of immunized mice. ( A) hs-TnT levels in serum of immunized mice. Wt and RAGE-ko mice were immunized with CFA or TnI. RAGE-ko mice were protected from developing TnI-induced EAM. Therefore, blockage of one of these molecules might represent a novel therapeutic strategy in the treatment of autoimmune myocarditis and inflammatory cardiomyopathy.įig. These findings could be confirmed by the clinical relevance of HMGB1 and sRAGE. Other receptors of HMGB1 such as Toll-like receptors (TLRs) may also be involved in disease pathogenesis. Moreover, the proinflammatory effect of HMGB1 is not necessarily dependent on RAGE only. 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. Finally, patients with myocarditis displayed increased local and systemic HMGB1 and soluble RAGE (sRAGE) expression. Moreover, cardiac overexpression of HMGB1 using adeno-associated virus (AAV) vectors induced inflammation in the hearts of both wt and RAGE-ko mice. Furthermore, RAGE knockout (RAGE-ko) mice immunized with TnI showed no structural or physiological signs of cardiac impairment. Additionally, pharmacological inhibition of HMGB1 using glycyrrhizin or anti-HMGB1 antibody reduced inflammation in hearts of TnI-immunized wt mice. 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. The involvement of the HMGB1–RAGE axis in the pathogenesis of inflammatory cardiomyopathy is yet not fully understood. 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). Autoimmune response to cardiac troponin I (TnI) induces inflammation and fibrosis in the myocardium. ![]()
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