Abstract 5851: Activation of Inflammatory and Apoptotic Pathways in Human Donor Heart Dysfunction
Donor heart dysfunction (DHD) precluding procurement for transplantation occurs in up to 25% of brain dead donors in the absence of structural heart disease. The molecular mechanisms of DHD remain unclear. We investigated the potential role of myocardial interleukin (IL)-6 signaling through the JAK2/STAT3 pathway which leads to the generation of nitric oxide (NO) and decreased cardiac myocyte contractility in vitro. NO can also lead to induction of the proapoptotic gene Bnip3 in vitro. Hearts were procured using standard technique with UW solution from 14 brain dead donors with a left ventricular ejection fraction of < 30% (DHD) in the absence of structural heart disease. Six hearts with normal function (NF) that were procured but not transplanted for non-cardiac reasons served as controls. Left ventricular (LV) IL-6 levels were quantitated by ELISA and signaling through the JAK2/STAT3 pathway via IL-6 and gp130 receptors was assessed by expression of activated, or phosphorylated STAT3. NO signaling was measured by myocardial expression of inducible NO synthase (iNOS) and protein immunoblotting for Bnip3 was performed. Myocardial IL-6 protein levels were 8-fold greater in the DHD group vs. NF controls (P< 0.02). Phosphorylated STAT3 expression was 5-fold higher in DHD vs. NF (P< 0.01) indicating increased JAK2/STAT3 signaling as there was no difference in total STAT3 expression between groups (P>0.05). LV expression of iNOS was 2-fold greater in DHD vs. NF (P< 0.03) consistent with increased iNOS activity. In addition, LV expression of the proapoptotic gene Bnip3 was 3-fold greater in the DHD group vs. NF (P< 0.04) suggesting that apoptosis may contribute to DHD. N= 14 for DHD and n= 6 for NF in all studies. Increased myocardial IL-6-mediated signaling through the JAK2/STAT3 pathway leading to upregulation of iNOS and NO production may be an important mechanism in human DHD. Increased myocardial NO also appears to lead to upregulation of proapoptotic Bnip3 in cardiac myocytes, and apoptotic cell death may also contribute to ventricular dysfunction following brain death. Inhibition of IL-6/JAK2/STAT3 signaling may represent a novel strategy to increase the severely limited number of cardiac donors.