Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia.

OBJECTIVES: Cancer cachexia affects the majority of tumor patients and significantly contributes to high mortality rates in these subjects. Despite its clinical importance, the identity of tumor-borne signals and their impact on specific peripheral organ systems, particularly the heart, remain mostly unknown. METHODS AND RESULTS: By combining differential colon cancer cell secretome profiling with large-scale cardiomyocyte phenotyping, we identified a signature panel of seven "cachexokines", including Bridging integrator 1, Syntaxin 7, Multiple inositol-polyphosphate phosphatase 1, Glucosidase alpha acid, Chemokine ligand 2, Adamts like 4, and Ataxin-10, which were both sufficient and necessary to trigger cardiac atrophy and aberrant fatty acid metabolism in cardiomyocytes. As a prototypical example, engineered secretion of Ataxin-10 from non-cachexia-inducing cells was sufficient to induce cachexia phenotypes in cardiomyocytes, correlating with elevated Ataxin-10 serum levels in murine and human cancer cachexia models. CONCLUSIONS: As Ataxin-10 serum levels were also found to be elevated in human cachectic cancer patients, the identification of Ataxin-10 as part of a cachexokine cocktail now provides a rational approach towards personalized predictive, diagnostic and therapeutic measures in cancer cachexia.

Mucosal tolerance induction in autoimmune myocarditis and myocardial infarction.

BACKGROUND: Antigen-specific therapy is a compelling approach for the treatment of autoimmune conditions. Primary goal is to induce the specific tolerization of self-reactive immune cells without altering host immunity against pathogens. We studied the effects of mucosal tolerance induction on cTnI-induced experimental autoimmune myocarditis (EAM) and post-infarct remodeling. METHODS: Mucosal tolerance was induced by intranasal application of cTnI, alternatively anti-CD3 p.o. Protocols varied in frequency, dosage and time point of application before EAM. We then applied the most effective regimen to mice undergoing myocardial infarction in order to verify its effectiveness in post-infarct cardiac remodeling. The myocardium was evaluated on histological slides and for the cytokine secretion pattern, while echocardiography determined cardiac function. RESULTS: A single dose of 100 µg of cTnI 7 days prior to myocarditis appeared to be most effective in suppressing inflammation and fibrosis (p = 0.03), while improving fractional shortening (p = 0.02). Treatment with intranasal cTnI upregulated IL-10 expression. On the other hand, frequent intranasal application of high doses of cTnI increased myocardial inflammation. Anti-CD3 p.o. showed the propensity to reduce myocardial inflammation and improve cardiac function. The single dose regimen of i.n. cTnI applied 7 days before a myocardial infarction reduced inflammation by trend (p=0.07) and improved heart function (p=0.002). Moreover, expression of matrix metalloproteinases 9 and 14 significantly decreased when treated with intranasal cTnI (p<0.01). CONCLUSIONS: Depending on the optimal amount, the time period and the choice of antigen, effective mucosal tolerance can be achieved and represents an appealing therapeutic approach in the inflammatory process of cardiac remodeling.

S100A8/A9 aggravates post-ischemic heart failure through activation of RAGE-dependent NF-κB signaling.

The extracellular heterodimeric protein S100A8/A9 activates the innate immune system through activation of the receptor of advanced glycation end products (RAGE) and Toll-like receptors. As activation of RAGE has recently been associated with sustained myocardial inflammation and heart failure (HF) we studied the role of S100A8/A9 in the development of post-ischemic HF. Hypoxia led to sustained induction of S100A8/A9 accompanied by increased nuclear factor (NF-)κB binding activity and increased expression of pro-inflammatory cytokines in cardiac fibroblasts and macrophages. Knockdown of either S100A8/A9 or RAGE rescued the induction of pro-inflammatory cytokines and NF-κB activation after hypoxia. In a murine model of post-ischemic HF both cardiac RNA and protein levels of S100A8/A9 were elevated as soon as 30 min after hypoxia with sustained activation up to 28 days after ischemic injury. Treatment with recombinant S100A8/A9 resulted in reduced cardiac performance following ischemia/reperfusion. Chimera experiments after bone marrow transplantation demonstrated the importance of RAGE expression on immune cells for their recruitment to the injured myocardium aggravating post-ischemic heart failure. Signaling studies in isolated ventricles indicated that MAP kinases JNK, ERK1/2 as well as NF-κB mediate signals downstream of S100A8/A9-RAGE in post-ischemic heart failure. Interestingly, cardiac performance was not affected by administration of S100A8/A9 in RAGE(-/-)-mice, which demonstrated significantly improved cardiac recovery compared to WT-mice. Our study provides evidence that sustained activation of S100A8/A9 critically contributes to the development of post-ischemic HF driving the progressive course of HF through activation of RAGE.

HMGB1 is associated with atherosclerotic plaque composition and burden in patients with stable coronary artery disease.

OBJECTIVES: The role of inflammation in atherosclerosis is widely appreciated. High mobility group box 1 (HMGB1), an injury-associated molecular pattern molecule acting as a mediator of inflammation, has recently been implicated in the development of atherosclerosis. In this study, we sought to investigate the association of plasma HMGB1 with coronary plaque composition in patients with suspected or known coronary artery disease (CAD). DESIGN: HMGB1, high sensitive troponin T (hsTnT) and high sensitive C-reactive protein (hsCRP) were determined in 152 consecutive patients with suspected or known stable CAD who underwent clinically indicated 256-slice coronary computed tomography angiography (CCTA). Using CCTA, we assessed 1) coronary calcification, 2) non-calcified plaque burden and 3) the presence of vascular remodeling in areas of non-calcified plaques. RESULTS: Using univariate analysis, hsCRP, hsTnT and HMGB1 as well as age, and atherogenic risk factors were associated with non-calcified plaque burden (r = 0.21, p = 0.009; r = 0.48, p<0.001 and r = 0.34, p<0.001, respectively). By multivariate analysis, hsTnT and HMGB1 remained independent predictors of the non-calcified plaque burden (r = 0.48, p<0.01 and r = 0.34, p<0.001, respectively), whereas a non-significant trend was noticed for hs-CRP (r = 0.21, p = 0.07). By combining hsTnT and HMGB1, a high positive predictive value for the presence of non-calcified and remodeled plaque (96% and 77%, respectively) was noted in patients within the upper tertiles for both biomarkers, which surpassed the positive predictive value of each marker separately. CONCLUSIONS: In addition to hs-TnT, a well-established cardiovascular risk marker, HMGB1 is independently associated with non-calcified plaque burden in patients with stable CAD, while the predictive value of hs-CRP is lower. Complementary value was observed for hs-TnT and HMGB1 for the prediction of complex coronary plaque.

HMGB1: the missing link between diabetes mellitus and heart failure.

Diabetes mellitus (DM) is a major independent risk factor for cardiovascular disease, but also leads to cardiomyopathy. However, the etiology of the cardiac disease is unknown. Therefore, the aim of this study was to identify molecular mechanisms underlying diabetic heart disease. High glucose treatment of isolated cardiac fibroblasts, macrophages and cardiomyocytes led to a sustained induction of HMGB1 on the RNA and protein level followed by increased NF-κB binding activity with consecutively sustained TNF-α and IL-6 expression. Short interference (si) RNA knock-down for HMGB1 and RAGE in vitro confirmed the importance of this axis in diabetes-driven chronic inflammation. In a murine model of post-myocardial infarction remodeling in type 1 diabetes, cardiac HMGB1 expression was significantly elevated both on RNA and protein level paralleled by increased expression of pro-inflammatory cytokines up to 10 weeks. HMGB1-specific blockage via box A treatment significantly reduced post-myocardial infarction remodeling and markers of tissue damage in vivo. The protective effects of box A indicated an involvement of the mitogen-activated protein-kinases jun N-terminal kinase and extracellular signal-regulated kinase 1/2, as well as the transcription factor nuclear factor-kappaB. Interestingly, remodeling and tissue damage were not affected by administration of box A in RAGE(-/-) mice. In conclusion, HMGB1 plays a major role in DM and post-I/R remodeling by binding to RAGE, resulting in activation of sustained pro-inflammatory pathways and enhanced myocardial injury. Therefore, blockage of HMGB1 might represent a therapeutic strategy to reduce post-ischemic remodeling in DM.