IL‐6 modulates cardiac muscle proteostasis and anti‐oxidative capacity post‐burn

Abstract

Heart failure is the number one cause of death in severely burned patients. Burn‐induced cardiac dysfunction includes increased cardiac work, tachycardia and increased energy expenditure. Burn injury induces a surge in catecholamine and cytokines levels that lasts up to 3 years post injury. While cardiac dysfunction has been associated with stimulation of the β‐adrenergic receptors (β‐ARs) by catecholamines, the role of inflammatory cytokines in the cardiac muscle function is still unclear. We have reported that burn injury alters the beta‐adrenergic signaling in the heart at 7 days post‐burn. In another study, we have shown that burn injury induces atrophy of the diaphragm muscle through activation of the IL‐6/JAK/Stat pathway.Male wild‐type and interleukin 6 knockout mice (IL‐6 KO) were subjected to a 30% total body surface area full‐thickness burn. Animals were sacrificed 10 days post injury. The hearts were isolated and western blotting performed to analyze the role of JAK/Stat signaling pathways and antioxidant enzymes in cardiac muscle proteostasis post‐burn.Burn injury significantly increases Stat‐3 phosphorylation at Ser 727 in the WT (p<0.05) but not in the IL‐6‐KO animals. Stat‐3 phosphorylation at tyrosine705 (Y705) was activated in the cardiac muscle of both the WT (p<0.05) and IL‐6 KO (p<0.05) mice post‐burn. At basal levels, p‐Stat‐3(Y705) was higher in the control IL‐6 KO than the control WT animals (p< 0.05). P‐Stat‐3 (Y705) levels were also higher in L‐6 KO burned animals compared to WT burned animals (p<0.01). The protein levels of antioxidant enzymes SOD‐2 and catalase were significantly decreased post‐burn in the WT (both p<0.05) but not in the IL‐6 KO animals.These data suggest that the molecular mechanisms regulating cardiac muscle proteostasis and anti‐oxidative capacity following burn injury are altered in the IL‐6‐KO mice supporting the role of IL‐6 as a critical mediator in these processes.Support or Funding InformationThis study was supported by grants from the National Institute of Health (P50‐GM60338, R01‐GM56687, and T32‐GM8256, NIH R01 GM 112936‐01, UL1TR000071), Shriners Hospitals for Children (71008, 71001 and 84080), and the Shriners Hospital for Children fellowship for AE (SHC 84202).