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.