Heat Shock Protein Expression During Cardiac Surgery

There has been a great deal of interest in a group of cellular proteins collectively called heat shock proteins (HSPs) to identify their role in the inflammatory and cell-mediated responses that occur during heart surgery [1]. Although most patients do fine after cardiopulmonary bypass (CPB), some develop an inflammatory response clinically resembling a sepsis-like state. At the cellular level, several stressrelated proteins, clustered as HSPs, participate in the inflammatory cascade mostly by acting as chaperons. Their basic role is to maintain the structural integrity of proteins under stress states by keeping them in their folded state, but their overexpression can lead to an inflammatory response. The ex vivo environment created during CPB exposes blood to nonendothelial circuitry, thereby triggering responses in the complement, coagulation, and humoral cascades. Chaperone HSPs play a significant role in inciting and modulating these triggers and responses. HSP-60, for example, is mostly intracellular; but in stress states it is overexpressed on endothelial cells. This protein is taken up by macrophages, which in turn cause it to trigger the immune system by signaling T and B lymphocytes. An HSP-60 lipopolysaccharide (LPS) complex then activates dendritic cells, causing release of interferon-c (INFc) and interleukin-12 (IL-12). This complex depends on toll-like receptors (TLRs) to gain entry into the cell via CD14 receptors. TLR 2, along with HSP-60, causes a T-cell response that down-regulates the secretion of tumor necrosis factor-a (TNFa) and INF c and up-regulates the secretion of transforming growth factor-b (TGFb) and IL-10. Intracellularly, the HSP60–LPS complex assembles nuclear factor jB (NF-jB) components, which in turn lead to initiation of cytokines, chemokines, and growth factor synthesis. This cascade leads to the hyperdynamic sepsislike syndrome sometimes seen following CPB. The HSP-70s are yet another complex set of proteins that include HSP-73, HSP-72, HSP-70 (which is stress inducible), and HSP70L1. This HSP family, however, is protective in nature. In stress states, HSP-70 enters the nucleus and activates poly (ADP-ribose) polymerase enzyme, involved in DNA repair. Overexpression of the latter enzyme can cause cellular energy depletion by overconsumption of ATP and NAD? often seen after rapid reperfusion. The deleterious effects of poly (ADP-ribose) polymerase can be neutralized by HSP-70 synthesized by inducing heat shock. This family of proteins also stabilizes the membranes of lysosomes, thereby preventing autolysis and apoptosis. HSP-70 is released into the extracellular compartment and also uses the CD-14 receptor along with TLR-2 and TLR-4 to stimulate nucleic synthesis of NK-jB, ultimately leading to monocyte stimulation. HSP70 is detected after cardiac surgery and more so during myocardial damage wherein high expression correlates with high creatine kinase, myocardial bound (CK-MB) and troponin-T levels. Its expression peaks 2 h after surgery and is fourfold lower during off-pump heart surgery compared to on-pump heart surgery. This is unlike HSP-60 levels, which seem to be unaffected regardless of whether CPB is used [2]. Other proteins that are increased during CPB include HSP-27, which prevents apoptosis by halting activation of caspase through sequestering cytochrome c and procaspase 3 and by stabilizing the cytoskeleton. Its levels rise with stress and decline when stress is attenuated; and it is increased twofold with use of CPB. HSP-90a is another A. Z. Chaudhry M. D. Diodato M. G. Massad (&) Division of Cardiothoracic Surgery, University of Illinois at Chicago, 840 S. Wood Street, CSB Suite 417(MC 958), Chicago, IL 60612, USA e-mail: mmassad@uic.edu