Effects of HMGB1 on Ischemia-Reperfusion Injury in the Rat Heart

Abstract

yocardial infarction is a disease that remains highly lethal despite recent advanced medical treatment. It is caused by the sudden interruption of coronary flow by occlusion of the coronary artery, which sequentially causes irreversible cardiomyopathy, tissue loss, and scar formation. Various pharmacological or surgical therapies have been reported for ischemia-reperfusion (I/R) injury, 1 and recent investigations have revealed the involvement of nitric oxide in myocardial injury during coronary reperfusion. 2 Moreover, I/R induces an inflammatory response and cytokine release from inflammatory cells, such as monocytes, macrophages and leukocytes, 3 but there is still no satisfactory protective therapy for I/R injury by regulating inflammation.High-mobility group box 1 protein (HMGB1) is a nonhistone DNA-binding, multifunctional protein that has both nuclear and extracellular functions. HMGB1 was originally identified as a DNA-binding protein, and was described as a multifunction transcriptional factor (amphoterin) that interacted with DNA. 4 In addition, HMGB1 has a binding site for the receptor for advanced glycation end-products (RAGE), which was originally identified as a receptor for the AGEs that accumulate during hyperglycemia. 5,6 Consequently, HMGB1-deficient mice die of hypoglycemia within 24 h of birth, suggesting that HMGB1 is associated with glycemic homeostasis. 7 Nuclear HMGB1 is released into the extracellular space during inflammatory responses that markedly and extensively activate macrophages and monocytes, as well as from necrotic cells, being released in sepsis. [8][9][10] Recent animal model studies have shown that HMGB1 is associated with I/R injury in several organs. 11 In liver I/R injury in the rat, plasma HMGB1 levels were increased at the early time point of 1 h after reperfusion and thereafter further increased in a time-dependent manner for 24 h. Treatment with a neutralizing antibody to HMGB1 significantly decreased liver damage after reperfusion injury. 12,13 In cerebral I/R injury in the rat, extracellular HMGB1 prevented expansion of the lesion during acute neuronal damage processes, and treatment with anti-HMGB1 antibody improved brain infarction post-treatment. 14 In I/R injury of the heart, cardiomyocyte inflammatory receptors are stimulated by pro-inflammatory mediators. 15 Recent studies have suggested that I/R injury may be attenuated through therapeutic targeting of these inflammatory receptors, such as RAGE, toll-like receptor (TLR) 2, and TLR4. [16][17][18] These observations predict that blocking the HMGB1 signal may protect the heart from I/R injury. However, another study of HMGB1 showed that exogenous HMGB1 induced myocardial cell proliferation and differentiation in the infarcted heart tissue. 19 In the present study, neutralizing anti-HMGB1 monoclonal antibody (mAb) was used to elucidate the role of HMGB1 in cardiac I/R injury. Background Coronary ischemia-reperfusion (I/R) injury causes cardiomyocyte necrosis in a multi-step process that includes an inflammatory ...

Extracellular high‐mobility group box 1 mediates pressure overload‐induced cardiac hypertrophy and heart failure

“…There exist growing recognition and experimental evidence to support that HMGB1 plays a pivotal role not only in the diseases such as sepsis, autoimmune disease, acute hepatic necrosis, acute lung injury 25, 26, 27, 28 but also in various heart diseases, including myocardial infarction and ischaemia‐reperfusion injury, however, with no consensus on the function of HMGB1 on the pathogenesis of the diseases 9, 16, 29, 30, 31, 32, 33, 34.…”

Ischemia Enhances Translocation of Connexin43 and Gap Junction Intercellular Communication, Thereby Propagating Contraction Band Necrosis After Reperfusion

“…The left anterior descending coronary artery (LAD) of male Sprague-Dawley rats aged 8 weeks was occluded as previously described. 21,24 The ECG (leads I-III) was monitored throughout the experiment. Rats in which arrhythmic events (PVCs, short runs of VT, and occurrence of VF) were observed during the early period (5-10 min) of ischemia were used in subsequent analyses.…”

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

“…HMGB1 binds to the endogenous receptor for advanced glycation endproducts [7], exogenous toll-like receptor 2/4/9 (TLR2/4/9) [8,9], and CD24/Siglec-10 [10], and induces the expression of proinammatory cytokines, chemokines, and adhesion molecules [3,6]. Although, HMGB1 was initially thought to be a late mediator of sepsis, recent data also indicated that HMGB1 is associated with many other pathological conditions, such as autoimmune disease [11], cancer [12][13][14], trauma, ischemia-reperfusion injury [15,16], tissue repair and regeneration [17,18], and cardiovascular diseases [19]. Furthermore, HMGB1 has restorative effects on CD4 1 T-helper cell modulation [20].…”

“…thought to be a late mediator of sepsis, recent data also indicated that HMGB1 is associated with many other pathological conditions, such as autoimmune disease [11], cancer [12][13][14], trauma, ischemia-reperfusion injury [15,16], tissue repair and regeneration [17,18], and cardiovascular diseases [19]. Furthermore, HMGB1 has restorative effects on CD4 1 T-helper cell modulation [20].…”