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. 2013 Apr;216(4):719-26; discussion 726-9.
doi: 10.1016/j.jamcollsurg.2012.12.034. Epub 2013 Feb 13.

Activation of the homeostatic intracellular repair response during cardiac surgery

Salik M Jahania  1 , David Sengstock, Peter Vaitkevicius, Allen Andres, Bruce R Ito, Roberta A Gottlieb, Robert M Mentzer Jr
Affiliations

Activation of the homeostatic intracellular repair response during cardiac surgery

Salik M Jahania et al. J Am Coll Surg. 2013 Apr.

Abstract

Background: The homeostatic intracellular repair response (HIR2) is an endogenous beneficial pathway that eliminates damaged mitochondria and dysfunctional proteins in response to stress. The underlying mechanism is adaptive autophagy. The purpose of this study was to determine whether the HIR2 response is activated in the heart in patients undergoing cardiac surgery and to assess whether it is associated with the duration of ischemic arrest and predicted surgical outcomes.

Study design: Autophagy was assessed in 19 patients undergoing coronary artery bypass or valve surgery requiring cardiopulmonary bypass. Biopsies of the right atrial appendage obtained before initiation of cardiopulmonary bypass and after weaning from cardiopulmonary bypass were analyzed for autophagy by immunoblotting for LC3, Beclin-1, autophagy 5-12, and p62. Changes in p62, a marker of autophagic flux, were correlated with duration of ischemia and with the mortality/morbidity risk scores obtained from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (version 2.73).

Results: Heart surgery was associated with a robust increase in autophagic flux indicated by depletion of LC3-I, LC3-II, Beclin-1, and autophagy 5-12; the magnitude of change for each of these factors correlated significantly with changes in the flux marker p62. In addition, changes in p62 correlated directly with cross-clamp time and inversely with the mortality and morbidity risk scores.

Conclusions: These findings are consistent with preclinical studies indicating that HIR2 is cardioprotective and reveal that it is activated in patients in response to myocardial ischemic stress. Strategies designed to amplify HIR2 during conditions of cardiac stress might have a therapeutic use and represent an entirely new approach to myocardial protection in patients undergoing heart surgery.

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Figures

Figure 1
Figure 1
Autophagy Machinery Involved in HIR2. Initiation of autophagy involves the participation of autophagy (Atg) proteins involved in formation of the pre-autophagosomal structure and elongation of the isolation membrane. Atg12 is covalently linked to Atg5 by a ubiquitin ligase system (Atg7, Atg10). Damaged mitochondria, protein aggregates, and other cytosolic components are flagged for engulfment by the adaptor protein p62. The autophagosome fuses with a lysosome and the cargo is degraded along with many of the Atg proteins. Under conditions of rapid autophagic flux, Atg proteins may be consumed before they can be replaced by new protein synthesis.
Figure 2
Figure 2
Reduced Levels of Beclin-1 during Cardiac Stress. Graph shows densitometry values for Beclin-1 from right atrial appendage biopsies taken before and after CPB for each patient. Lower panel shows representative Western blots from 7 of the 19 patients. Arrow indicates Beclin-1.
Figure 3
Figure 3
Reduced Levels of Atg5-12 during Cardiac Stress. Graph shows densitometry values for Atg5-12 from right atrial appendage biopsies taken before and after CPB for each patient. Lower panel shows representative Western blots from 7 of the 19 patients. Arrow indicates Atg5-12.
Figure 4
Figure 4
Reduced Levels of p62 during Cardiac Stress. Graph shows densitometry values for p62 from right atrial appendage biopsies taken before and after CPB for each patient. Lower panel shows representative Western blots from 7 of the 19 patients. Arrow indicates p62.
Figure 5
Figure 5
Autophagy Protein Depletion Is Coordinated. Each graph shows the change in the indicated autophagy protein (e.g. ΔBeclin-1) plotted against the change in p62 (Δp62) for each patient.
Figure 6
Figure 6
Depletion of p62 as a Function of Cross Clamp Time. Plot shows linear regression analysis of Δp62 vs. cross clamp time (p=0.0696). Each point corresponds to an individual patient. With multivariate analysis to take the starting level of p62 into account, there was a statistically significant association between the second p62 level and cross clamp time (r2 =0.3785; p=0.0384).
Figure 7
Figure 7
Operative Risk Correlates with Changes in Autophagy. Plot shows linear regression of morbidity and mortality risk score versus Δp62. Each point represents an individual patient.
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