Various pediatric and adult cardiovascular operations involve cardiopulmonary bypass (CPB) procedures that require a period of circulatory arrest. Major cardiovascular surgery in pediatric and adult patients induces perioperative organ injury and is therefore associated with significant adverse cerebral, renal and cardiovascular outcomes. To protect organs from ischemic damage, surgery is usually performed during deep hypothermic conditions (deep hypothermic circulatory arrest, DHCA). Although the protective potential of deep hypothermia is unquestionable, little is known about the mechanisms through which it protects organs or how to maximize its efficacy. Elucidating the mechanisms underlying protection of organs by deep hypothermia is therefore of tremendous clinical interest. If we understood these mechanisms, we would be able to design therapeutic strategies to activate such processes and thus induce a state of tolerance without risking the adverse effects associated with deep hypothermia. We hypothesize that deep hypothermia protects organs from ischemic damage by activating the small ubiquitin-like modifier (SUMO) conjugation pathway. Protein sumoylation markedly influences the stability, localization and activity of transcription factors and other intracellular proteins. Deep hypothermia-induced changes in SUMO conjugation may therefore play a key role in defining the final outcome of cells exposed to transient DHCA. We found a marked increase in levels of SUMO conjugated proteins during deep hypothermia, and activation of SUMO conjugation has been shown to protect cells from damage induced by ischemia-like conditions. We have the following Specific Aims: 1) To examine the relationship between extent and duration of hypothermia and activation of the SUMO conjugation pathway;2) To identify proteins in which SUMO conjugation is activated by hypothermia;3) To verify whether by silencing SUMO expression and thus blocking deep hypothermia-induced activation of the SUMO conjugation pathway, it is possible to modify the sensitivity of organs to DHCA. It is widely believed that hypothermia-induced protection is a passive process whereby the rate of glucose metabolism is lowered and the time to terminal depolarization consequently increased. This would shorten the period of terminal depolarization and thus mitigate all pathological processes triggered during the state of energy depletion and manifested after recovery from ischemia. If our hypothesis proves valid, i.e. deep hypothermia does indeed induce an active process resulting in a rise in levels of SUMO conjugated proteins and activation of the SUMO conjugation pathway does play a key role in that process, it could revolutionize our understanding of the mechanisms underlying the protective effects of hypothermia. SUMO conjugation could represent an exciting new target for therapeutic intervention by providing a means of increasing the resistance of organs to a transient interruption of blood supply.

Public Health Relevance

Circulatory arrest is required for various surgeries, including aortic surgery or correction of congenital heart defects in the neonates. To protect organs from damage caused by transient ischemia, circulatory arrest is carried out under deep hypothermic conditions. This proposal focuses on the hypothesis that activation of small ubiquitin-like modifier (SUMO) conjugation of target proteins plays a major role in deep hypothermiainduced organ protection. If our hypothesis proves valid, SUMO conjugation could prove to be a very exciting new target for therapeutic intervention by providing a means of increasing the resistance of organs to a transient interruption of blood supply.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095552-03
Application #
8217294
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Sopko, George
Project Start
2010-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$386,100
Indirect Cost
$138,600
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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