Exosomes in aging and operative hypothermic circulatory arrest

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ABSTRACT Aged patients are susceptible to cellular stress events associated with surgery. Exosomes represent a new paradigm in the cellular stress response that has only recently begun to be addressed in the surgical population. Exosomes are released by cells in response to numerous stimuli including cell stress and carry a cargo of biologically active molecules including DNA, RNA, proteins, lipids, cytokines, growth factors and metabolites. The role of exosomes in the aging surgical population is unknown and may have major impact on perioperative care. Deep hypothermic circulatory arrest (DHCA) is a profound perioperative stress event involving isolation of the systemic vasculature via cardiopulmonary bypass and arrest of the circulation to major organ systems. There is no information available regarding the release of exosomes as a result of the stress of whole body ischemia and reperfusion after DHCA in patients and most importantly as a function of age. At the University of California, San Diego we perform DHCA in conjunction with pulmonary thromboendarterectomy (PTE) surgery. Our clinical volume of 200 PTE surgeries per year results in patients with a range of ages (18- 80 years old) undergoing DHCA. We will test the novel hypothesis that surgically induced DHCA increases the release of exosomes, alters the characteristics of the exosome profile, and alters the ability of exosomes to affect cellular metabolism and function in an age dependent manner. In the proposal we will: 1) Determine the characteristics and content of exosomes released from patients before and after DHCA and address the potential role of patient age on the release and content of exosomes, and 2) Assess the potential of exosomes released from different age groups in response to DHCA to affect metabolism and function in human endothelial cells. The work will combine expertise from anesthesia, surgery, medicine and basic science disciplines and promote the future investigation of innovative hypotheses and novel therapies for the organismal response to ischemia-reperfusion injury in aged patients.