Antibody against interleukin-6 receptor attenuates left ventricular remodelling after myocardial infarction in mice.
ABSTRACT The plasma level of interleukin-6 (IL-6) has been reported to be associated with left ventricular (LV) remodelling after myocardial infarction (MI). The present study was designed to examine whether anti-IL-6 receptor antibody (MR16-1) prevents the development of LV remodelling after MI.
Balb/c male mice were subjected to MI by ligating the left anterior descending coronary artery. The mice were then treated with an intraperitoneal injection of MR16-1 (500 microg/body) or control IgG. MR16-1 decreased the myocardial myeloperoxidase activity and monocyte chemoattractant protein-1 concentration in the infarct region, concomitant with decreases in neutrophil and macrophage infiltration 3 days after ligation, while infarct size was comparable between the control IgG- and MR16-1-treated mice. At 7 days after ligation, MR16-1 significantly suppressed matrix metalloproteinase-2 activity in the infarct region. Furthermore, the MR16-1-treated mice demonstrated a reduction in LV dilatation and an improvement in LV contractile function compared with the control IgG-treated mice at 7 and 28 days after surgery, leading to an improvement in survival rate (80.6 vs. 59.5%, P < 0.05) at 28 days after surgery. The beneficial effects of MR16-1 were accompanied by histological suppression of cardiomyocyte hypertrophy and interstitial fibrosis in the non-infarct region.
Administration of MR16-1 after MI suppressed myocardial inflammation, resulting in the amelioration of LV remodelling. Neutralization of the IL-6 receptor is a potentially useful strategy for protecting hearts from LV remodelling after MI.
- SourceAvailable from: Xiangdong Cui[Show abstract] [Hide abstract]
ABSTRACT: We have previously shown that MyD88 KO mice appear protected from ischemic muscle injury while TRIF KO mice exhibit sustained necrosis after femoral artery ligation (FAL). However, our previous data did not differentiate whether the protective effect of absent MyD88 signaling was secondary to attenuated injury after FAL or quicker recovery from the insult. The purpose of this study was to delineate these different possibilities. On the basis of previous findings, we hypothesized that MyD88 signaling promotes enhanced inflammation while TRIF mediates regeneration after skeletal muscle ischemia. Our results show that after FAL, both MyD88 KO mice and TRIF KO mice have evidence of ischemia, as do their control counterparts. However, MyD88 KO mice had lower levels of serum IL-6 24 h after FAL, while TRIF KO mice demonstrated sustained serum IL-6 up to 1 week after injury. Additionally, MyD88 KO mice had higher nuclear content and larger myofibers than control animals 1 week after injury. IL-6 is known to have differential effects in myoblast function, and can inhibit proliferation and differentiation. In tibialis anterior muscle harvested from injured animals, IL-6 levels were higher and the proliferative marker MyoD was lower in TRIF KO mice by PCR. Furthermore, expression of MyD88 appeared to be higher in skeletal muscle of TRIF KO mice. In vitro, we showed that myoblast differentiation and proliferation were attenuated in response to IL-6 treatment giving credence to the finding that low IL-6 in MyD88 KO mice may be responsible for larger myocyte sizes 1 week after FAL. We conclude that MyD88 and TRIF work in concert to mediate a balanced response to ischemic injury.Physiological Reports. 05/2014; 2(5).
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ABSTRACT: High-mobility group box 1 (HMGB1) is a proinflammatory mediator playing an important role in the pathogenesis of cardiac dysfunction in many diseases. In this study, we explored the effects of HMGB1 on Ca(2+) handling and cellular contractility in cardiomyocytes to seek for the mechanisms underlying HMGB1-induced cardiac dysfunction. Our results show that HMGB1 increased the frequency of Ca(2+) sparks, reduced the sarcoplasmic reticulum (SR) Ca(2+) content, and decreased the amplitude of systolic Ca(2+) transient and myocyte contractility in dose-dependent manners in adult rat ventricular myocytes. Inhibiting high-frequent Ca(2+) sparks with tetracaine largely inhibited the alterations of SR load and Ca(2+) transient. Blocking toll-like receptor 4 (TLR4) with TAK-242 or knockdown of TLR4 by RNA interference remarkably inhibited HMGB1 induced high-frequent Ca(2+) sparks and restored the SR Ca(2+) content. Concomitantly, the amplitude of systolic Ca(2+) transient and myocyte contractility were significantly increased. Furthermore, HMGB1 increased the level of intracellular reactive oxygen species (ROS) and consequently enhanced oxidative stress and CaMKII-activated phosphorylation (pSer2814) in ryanodine receptor 2 (RyR2). TAK-242 pretreatment significantly decreased intracellular ROS levels and oxidative stress and hyperphosphorylation in RyR2, similar to the effects of antioxidant MnTBAP. Consistently, MnTBAP normalized HMGB1-impaired Ca(2+) handling and myocyte contractility. Taken together, our findings suggest that HMGB1 enhances Ca(2+) spark-mediated SR Ca(2+) leak through TLR4-ROS signaling pathway, which causes partial depletion of SR Ca(2+) content and thence decreases systolic Ca(2+) transient and myocyte contractility. Prevention of SR Ca(2+) leak may be an effective therapeutic strategy for the treatment of cardiac dysfunction related to HMGB1 overproduction.Journal of Molecular and Cellular Cardiology 06/2014; · 5.15 Impact Factor
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ABSTRACT: The host response to both synthetic and biologically-derived biomaterials is a temporally regulated, complex process that involves multiple interacting cell types. This complexity has classically limited the efficacy of in vitro assays for predicting the in vivo outcome, necessitating the use of costly animal models for biomaterials development. The present study addressed these challenges by developing an in vitro assay that characterized the dynamic inflammatory response of human monocyte-derived-macrophages to biomaterials, coupled with quasi-mechanistic analysis in silico analysis; Principal Component Analysis (PCA) and Dynamic Network Analysis (DyNA). Synthetic and extracellular matrix (ECM) derived materials were evaluated using this method, and were then associated with the in vivo remodeling and macrophage polarization response in a rodent skeletal muscle injury model. PCA and DyNA revealed a distinct in vitro macrophage response to ECM materials that corresponded to constructive remodeling and an increased M2 macrophage presence in vivo. In contrast, PCA and DyNA suggested a response to crosslinked ECM and synthetic materials characteristic of a foreign body reaction and dominant M1 macrophage response. These results suggest that in silico analysis of an in vitro macrophage assay may be useful as a predictor for determining the in vivo host response to implanted biomaterials.Tissue Engineering Part C Methods 07/2014; · 4.64 Impact Factor