Critical role of RAGE and HMGB1 in inflammatory heart disease

Bangert, Anna; Andrassy, Martin; Müller, Alexander; Bockstahler, Mariella; Fischer, Andrea; Volz, Christian; Leib, Christoph; Göser, Stefan; Korkmaz‐Icöz, Sevil; Zittrich, Stefan; Jungmann, Andreas; Lasitschka, Felix; Pfitzer, Gabriele; Müller, Oliver; Katus, Hugo A.; Kaya, Ziya

doi:10.1073/pnas.1522288113

Cited by 134 publications

(119 citation statements)

References 61 publications

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“…These studies suggest that a critical component of disease pathogenesis in EAM is the release of DAMPs that drive inflammatory responses resulting in impaired LV function. 155 Monocytes may play an important role in EAM progression as inhibition of monocyte recruitment via CCR2 siRNA resulted in decreased immune cell infiltration, fibrosis, and increased cardiac function. This was observed when siRNA was injected either at the onset of disease or 21 days post-EAM induction, suggesting that monocytes play a role even at later stages after disease establishment.…”

Section: Experimental Autoimmune Myocarditismentioning

confidence: 99%

Chronic Heart Failure and Inflammation

Dick

Epelman

2016

Circulation Research

523

380

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As a greater proportion of patients survive their initial cardiac insult, medical systems worldwide are being faced with an ever-growing need to understand the mechanisms behind the pathogenesis of chronic heart failure (HF). There is a wealth of information about the role of inflammatory cells and pathways during acute injury and the reparative processes that are subsequently activated. We discuss the different causes that lead to chronic HF development and how the sum of initial inflammatory and reparative responses only sets the trajectory for disease progression. Unfortunately, comparatively little is known about the contribution of the immune system once the trajectory has been set, and chronic HF has been established—which clinically represents the majority of patients. It is known that chronic HF is associated with circulating inflammatory cytokines that can predict clinical outcomes, yet the causative role inflammation plays in disease progression is not well defined, and the majority of clinical trials that target aspects of inflammation in patients with chronic HF have largely been negative. This review will present what is currently known about inflammation in chronic HF in both humans and animal models as a means to highlight the gap in our knowledge base that requires further examination.

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Section: Experimental Autoimmune Myocarditismentioning

confidence: 99%

Chronic Heart Failure and Inflammation

Dick

Epelman

2016

Circulation Research

523

380

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“…Banger et al found that HMGB1 or RAGE knockout mice showed decreased physiological signs of cardiac impairment after suffering from an autoimmune response to cardiac troponin I [34], suggesting a role for this signaling pathway in inflammatory and immune responses. Our research found that expression of both RAGE and the nuclear NF-κB p65 subunit in the rat cortex increased significantly at 12h and 24h after CLP.…”

Section: Discussionmentioning

confidence: 99%

Role of HMGB1 translocation to neuronal nucleus in rat model with septic brain injury

et al. 2017

Neuroscience Letters

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High-mobility Group Box-1 (HMGB1) is a central late proinflammatory cytokine that triggers the inflammatory response during sepsis. However, whether HMGB1 is involved in the pathogenesis of septic brain damage is unknown. In this study, we investigated the role of HMGB1 in regulating brain injury in a rat model of sepsis. Wistar rats were subjected to cecal ligation and puncture (CLP) to induce septic brain injury. Hematoxylin and eosin staining was used to detect pathological changes in the cortex. The cellular localization of HMGB1 was determined using immunostaining. Cortical levels of HMGB1, its receptor for advanced glycation end-products (RAGE), and downstream effecter, nuclear factor kappa-B (NF-κB) subunit p65, were detected via western blot.HMGB1was increased in the cytoplasm via translocation from the nucleus predominantly in neurons. Moreover, RAGE and NF-κB p65 were upregulated after septic brain injury. Ethyl pyruvate, an inhibitor of HMGB1, down-regulated the expression of RAGE and NF-κB p65via inhibiting HMGB1 expression in the cytoplasm. Collectively, our findings suggest that HMGB1 and its signaling transduction have critical roles in the pathogenesis of septic brain injury. HMGB1 inhibition might be a potential new therapeutic target for septic brain injury.

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“…The importance of RAGE in myocardial inflammation was demonstrated in a study where RAGEdeficient mice were shown to have a reduced myocardial damage compared with wild-type mice [45] . Moreover, ablation of RAGE leads to a reduction in several inflammatory mediators that is important for the pathogenesis of autoimmune myocarditis [26] . In addition to binding to RAGE and TLRs, HMGB1 can also bind to other cytokines such as interleukin-1β.…”

Section: Discussionmentioning

confidence: 99%

“…HMGB1 can also promote growth of atherosclerotic plaques by triggering smooth muscle cell migration and proliferation [23,24] and stimulates activation of endothelial cells by enhancing the expression of adhesive molecules and cytokines [25] . Moreover, a recent publication shows that patients with myocarditis display increased local and systemic HMGB1 expression, and blocking HMGB1 signaling in vitro can reduce cardiac inflammation in animal models [26] . Thus, HMGB1 seems to play important roles in the pathophysiology of cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Expression of High Mobility Group Protein B1 in Cardiac Tissue of Elderly Patients with Coronary Artery Disease with or without Inflammatory Rheumatic Disease

Bruton

Hollan²,

Xiao³

et al. 2017

Gerontology

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Background: It is known from clinical practice and observational studies that elderly patients with a diagnosis of inflammatory rheumatic diseases (IRD) bear a significantly increased risk for cardiovascular diseases such as coronary artery disease (CAD) and heart failure. The molecular mechanism, however, is still not known. Recently, high mobility group protein B1 (HMGB1), a ubiquitous, highly conserved single polypeptide expressed in all mammal eukaryotic cells, has been identified to mediate myocardial dysfunction in vitro once released from the nuclei of cardiomyocytes. Objective: To investigate whether HMGB1 and its receptors are expressed in cardiac muscles of elderly patients with CAD with or without IRD. Methods: HMGB1 and its 3 well-known receptors, receptor for advanced glycation end products, Toll-like receptor 2 (TLR2), and TLR4, were examined by immunohistochemistry on myocardial biopsy specimens from 18 elderly patients with CAD (10 with IRD, 8 without IRD). Furthermore, total HMGB1 protein levels were measured by Western blot from the cardiac biopsies in 5 patients with and 5 without IRD. Results: Pathologic cytosolic HMGB1 in cardiomyocytes was massively recorded in all patients with IRD, but only slightly expressed in 1 patient without IRD. Total HMGB1 levels were also consistently lower in myocardial muscle biopsies of patients with IRD compared to those without IRD. Furthermore, all 3 HMGB1 receptors were expressed in cardiomyocytes of all patients. Conclusion: The increased cytosolic expression of HMGB1 in cardiomyocytes and the lower total amount of HMGB1 in the cardiac specimens of IRD patients is consistent with a greater release of HMGB1 from the myocardial nuclei in IRD than non-IRD individuals. Thus, the HMGB1 signaling pathways may be more easily activated in elderly CAD patients with concomitant IRD and trigger a detrimental inflammatory process causing severe cardiovascular problems. Therefore, targeting HMGB1 in IRD patients might reduce the risk for cardiovascular events.

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Critical role of RAGE and HMGB1 in inflammatory heart disease

Cited by 134 publications

References 61 publications

Chronic Heart Failure and Inflammation

Chronic Heart Failure and Inflammation

Role of HMGB1 translocation to neuronal nucleus in rat model with septic brain injury

Expression of High Mobility Group Protein B1 in Cardiac Tissue of Elderly Patients with Coronary Artery Disease with or without Inflammatory Rheumatic Disease

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