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Human Cardiac Ischemia-Reperfusion Injury: Blunted Stress Response with Age
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  • Ashley Oliveira,
  • Bobby Yanagawa ,
  • Adrian Quan,
  • Subodh Verma,
  • David Hood
Ashley Oliveira
York University Faculty of Health
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Bobby Yanagawa
University of Toronto Faculty of Medicine
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Adrian Quan
St Michael's Hospital Keenan Research Centre for Biomedical Science
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Subodh Verma
University of Toronto Faculty of Medicine
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David Hood
York University Faculty of Health
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Abstract

Background & Aim: Autophagy is a cytoprotective recycling mechanism, capable of digesting dysfunctional cellular components, and this process is associated with pro-survival outcomes. Autophagy may decline in the aging myocardium, thereby contributing to cardiac dysfunction. However, it remains to be established how autophagy responds to ischemia-reperfusion stress with age. Methods: Samples from the right atrium were collected from young (≤50 years; n=5) and aged (≥70 years; n=11) patients prior to and immediately following cardioplegic arrest during coronary artery bypass grafting (CABG) surgery, a model of human ischemia-reperfusion injury. Results: Mitochondrial content did not differ between the age groups, however a 32% reduction in UQCRC2 (0.74 vs 0.53, effect of age, p=0.03) was seen with age, indicating possible compositional disruptions. In response to IR, VDAC (0.75 vs 1.05, p=0.03) and COX-I protein (0.63 vs 1.10, p=0.03) was over expressed in young, but not in aged patients. Reductions in Parkin (0.95 vs 0.49, interaction effect, p=0.04) and NIX (0.60 vs 0.21, p=0.004) protein expression with age suggest an impairment in mitochondrial recycling, which may lead to an accumulation of dysfunctional mitochondria. Following IR, our data suggest that in the young cohort, autophagy is reduced as a Beclin-1 decreased by 63% (0.95 vs 0.36, p=0.001) and no changes were observed in either p62 or LC3-II:I ratio. Conclusion: Our data demonstrate a blunted cardiac mitochondrial response to ischemia with age, accompanied by a possible impairment in mitophagy. These findings support an age-associated inability of the atrial myocardium to mount appropriate adaptive responses to stress.

Peer review status:UNDER REVIEW

12 Mar 2021Submitted to Journal of Cardiac Surgery
13 Mar 2021Submission Checks Completed
13 Mar 2021Assigned to Editor
17 Mar 2021Reviewer(s) Assigned
28 Apr 2021Review(s) Completed, Editorial Evaluation Pending
02 May 2021Editorial Decision: Revise Major
02 Jun 20211st Revision Received
04 Jun 2021Submission Checks Completed
04 Jun 2021Assigned to Editor
04 Jun 2021Reviewer(s) Assigned
12 Jun 2021Review(s) Completed, Editorial Evaluation Pending