Jinrong Fu, Guosheng Lin, Zhiwei Wu, Bin Ceng, Yanxia Wu, Gong Liang, Gangjian Qin, Jinan Li, Isaac Chiu, and Dongxu Liu. 2006. “
Anti-apoptotic role for C1 inhibitor in ischemia/reperfusion-induced myocardial cell injury.” Biochem Biophys Res Commun, 349, 2, Pp. 504-12.
AbstractComplement activation augments myocardial cell injury and apoptosis during ischemia/reperfusion (I/R), whereas complement system inhibition with C1 inhibitor (C1INH), a serine protease inhibitor, exerts markedly cardioprotective effects. Our recent data demonstrate that C1INH prevents vascular endothelial cell apoptosis and a "modified" form of the reactive center loop-cleaved, inactive C1INH (iC1INH) plays an anti-inflammatory role in endotoxin shock. The aim of this study was to determine whether C1INH protects against myocardial cell injury via an anti-apoptotic activity or anti-inflammatory effect. In a rat model of acute myocardial infarction (AMI) induced by I/R, administration of C1INH protected against cardiomyocytic apoptosis via normalization of ratio of the Bcl-2/Bax expression in the myocardial infarct area. C1INH improved parameters of cardiac function and hemodynamics and reduced myocardial infarct size (MIS). In addition, myocardial and blood myeloperoxidase (MPO) activity, a marker of neutrophil infiltration, was decreased by treatment of C1INH. In cultured H9c2 rat cardiomyocytic cells, C1INH blocked hypoxia/reoxygenation-induced apoptosis in the absence of sera associated with inhibition of cytochrome c translocation and suppression of caspase-3 activation. The proportion of Bcl-2/Bax expression induced by hypoxia/reoxygenation was reversed by C1INH. Importantly, iC1INH also revealed these similar effects, indicating that C1INH has a direct anti-apoptotic activity. Therefore, these studies support the hypothesis that C1INH, in addition to inhibition of activation of the complement and contact systems, improves outcome in I/R-mediated myocardial cell injury via an anti-apoptotic activity independent of serine protease inhibitory activity.
Ming Zhang, Elisabeth M Alicot, Isaac Chiu, Jinan Li, Nicola Verna, Thomas Vorup-Jensen, Benedikt Kessler, Motomu Shimaoka, Rodney Chan, Daniel Friend, Umar Mahmood, Ralph Weissleder, Francis D Moore, and Michael C Carroll. 2006. “
Identification of the target self-antigens in reperfusion injury.” J Exp Med, 203, 1, Pp. 141-52.
AbstractReperfusion injury (RI), a potential life-threatening disorder, represents an acute inflammatory response after periods of ischemia resulting from myocardial infarction, stroke, surgery, or trauma. The recent identification of a monoclonal natural IgM that initiates RI led to the identification of nonmuscle myosin heavy chain type II A and C as the self-targets in two different tissues. These results identify a novel pathway in which the innate response to a highly conserved self-antigen expressed as a result of hypoxic stress results in tissue destruction.
Yinghua Ma, Jianxue Li, Isaac Chiu, Yawen Wang, Jacob A Sloane, Jining Lü, Bela Kosaras, Richard L Sidman, Joseph J Volpe, and Timothy Vartanian. 2006. “
Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis.” J Cell Biol, 175, 2, Pp. 209-15.
AbstractToll receptors in Drosophila melanogaster function in morphogenesis and host defense. Mammalian orthologues of Toll, the Toll-like receptors (TLRs), have been studied extensively for their essential functions in controlling innate and adaptive immune responses. We report that TLR8 is dynamically expressed during mouse brain development and localizes to neurons and axons. Agonist stimulation of TLR8 in cultured cortical neurons causes inhibition of neurite outgrowth and induces apoptosis in a dissociable manner. Our evidence indicates that such TLR8-mediated neuronal responses do not involve the canonical TLR-NF-kappaB signaling pathway. These findings reveal novel functions for TLR8 in the mammalian nervous system that are distinct from the classical role of TLRs in immunity.