Abstract 110: Activation of the Homeostatic Intracellular Response Leads to Increased Myocardial Mitochondrial Turnover in Patients Undergoing Cardiac Surgery
Background: Previously we showed that the homeostatic intracellular repair response (HIR2) is activated in the hearts of patients undergoing cardiac surgery. Autophagy is a principal component of this beneficial response that clears fragile mitochondria and protein aggregates. Moreover, we have previously shown that mitochondrial elimination through autophagy (mitophagy) is a key element in ischemic preconditioning. Thus, an important mechanism of cardioprotection appears to involve the upregulation of autophagy which facilitates the clearance of vulnerable mitochondria to limit I/R injury. We hypothesized that this protective action leads to turnover of the existing mitochondrial population in the heart during the resolution of I/R injury. The purpose of this study was to examine if the mechanism of HIR2 extends to remodeling the existing mitochondrial population of the heart.
Study Design: Autophagy and mitochondrial turnover were assessed in 10 patients undergoing coronary artery bypass or valve surgery requiring cardiopulmonary bypass. Biopsies of the right atrial appendage obtained before initiation and after weaning from cardiopulmonary bypass were processed to yield whole tissue lysates and mitochondria-enriched heavy membrane fractions. Samples were analyzed for autophagy by immunoblotting for LC3, Beclin-1, ATG5-12, and p62. Mitochondrial turnover was assessed by monitoring Tom70, Cox4, Drp1, p62 and Parkin in tissue lysates and heavy membrane fractions.
Results: Heart surgery was associated with a robust increase in autophagy indicated by depletion of LC3, Beclin-1, ATG5-12 and p62, as well as the mitophagy and fission regulator Drp1. Parkin increased in the mitochondrial fraction after bypass. Surprisingly, post-bypass tissue lysates showed a marked increase in mitochondrial markers Tom70 and Cox4, suggesting mitochondrial biogenesis.
Conclusions: These findings provide evidence for the first time in humans that coordinated mitophagy and biogenesis are part of the homeostatic response to I/R, pointing to the importance of studying this aspect of HIR2. Strategies designed to amplify HIR2 during cardiac stress may represent an entirely new approach to myocardial protection in patients undergoing heart surgery.
Author Disclosures: A.M. Andres: None. D. Sengstock: None. S. Jahania: None. R. Dabir: None. R.A. Gottlieb: None. R.M. Mentzer: None.
- © 2015 by American Heart Association, Inc.