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GW24-e0624 Impairted cardiac SIRT1 activity by carbonyl stress increase susceptibility of aged hearts to ischaemia reperfusion injury
  1. Chunhu Gu1,
  2. Yuan Xing2,
  3. Lu Yu3,
  4. Heng Ma2
  1. 1Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University
  2. 2Department of Physiology, Fourth Military Medical University
  3. 3Department of Pathology, Xijing Hospital, Fourth Military Medical University

Abstract

Objectives Ageing increases susceptibility to myocardial ischaemia/reperfusion (I/R) injury. The present study is designed to evaluate the protective effects of ALDH2 activation on I/R tolerance in aged heart and to elucidate the underlying mechanisms with a focus on SIRT1.

Methods Male C57BL/6 young (4-6 mo) and aged (22-24 mo) mice were subjected to I/R (30 min/4h). Cardiac ALDH2, SIRT1 activity and aldehydes-protein adduct formation were assessed. Immunoblotting was used to evaluate the SIRT1 carbonylation.

Results Cardiac ALDH2 activity is impaired and toxic aldehydes (4-HNE)-protein adduct formation is enhanced with ageing (all P < 0.05). 4-HNE increased the carbonyl modifications on SIRT1 concomitant with decreased SIRT1 activity in vitro, and thus reduced myocardial tolerance to hypoxia/oxidative (all P < 0.05). But all these effects were blocked by Alda-1 (ALDH2 activator). The endogenous 4-HNE-protein adduct formation in aged hearts was 1.7-fold larger than that in young mice during I/Rin vivo. The levels of carbonylation on SIRT1 in I/R aged hearts was higher than that seen in their young counterparts. ALDH2 activation by Alda-1 significantly reduced the carbonylation on SIRT1 in the I/R aged hearts (P < 0.05). Alda-1 treatment significantly improved the tolerance of aged hearts to I/R injury, which was evidenced by reduced plasma creatine kinase activity and infarct size. However, Alda-1 treatment failed to decreased infarct size in Sirt1 +/− knockout mice hearts.

Conclusions These results provide a new insight that impaired cardiac SIRT1 activity by carbonyl stress plays a critical role in the increased susceptibility of aged heart to I/R injury. ALDH2 activation can restore this aging-related myocardial ischaemic intolernce.

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