Loss of Cardioprotection With Ischemic Preconditioning in Aging Hearts: Role of Sirtuin 1?

Abstract

The effectiveness of ischemic preconditioning (IPC) to protect the heart against ischemia/reperfusion injury (IRI) declines with age. The deacetylase protein sirtuin 1 (Sirt 1) confers myriad functions including longevity and cardioprotection against IRI. As such, Sirt 1 may be a potential candidate to explain the protective effect of IPC. We aim to explore the role of Sirt 1 in the loss of the cardioprotective effect of IPC with age. Isolated hearts from young (9 weeks) and older (12-18 months) Long-Evans rats were subjected to 30 minutes of global ischemia and 60 minutes of reperfusion. Preconditioning stimuli were applied with either 2 cycles of 5-minute ischemia/reperfusion or with the potent Sirt 1 agonist resveratrol (RSV, 10 µmol/L) for 15 minutes followed by a 10-minute washout before the sustained ischemia. Both IPC and RSV significantly enhanced the functional recovery of young hearts by 168% (P < .001 vs control) and 65% (P < .01 vs control), respectively, and concomitantly reduced the infarct size by 65% and 45%, but the effect was blunted in older hearts. Administration of the selective Sirt 1 inhibitor III to young hearts did not alter the protective effect of IPC. Following ischemia/reperfusion, higher Sirt 1 deacetylase activity was detected in older hearts compared to young hearts (0.48 ± 0.13 arbitrary units [AU] vs 0.17 ± 0.03 AU, P < .01) and IPC did not alter Sirt 1 deacetylase activity. In conclusion, although Sirt 1 deacetylase activity is increased with age during ischemia/reperfusion, our data suggest that the loss of the cardioprotective effect of IPC in older animals is likely to be independent of Sirt 1.

The age-associated loss of ischemic preconditioning in the kidney is accompanied by mitochondrial dysfunction, increased protein acetylation and decreased autophagy

“…Although experimental IPC models have been shown to evoke potent anti-ischemic defence47, IPC-induced protection is diminished in old animals, affording no protection in ischemic heart, brain and liver254849505152. Renal protection by IPC in aged animals has not been tested yet.…”

Mitochondrial function in hypoxic ischemic injury and influence of aging

“…The SIRT1 inhibitor splitomycin inhibited cardioprotection (Nadtochiy et al , 2011b). The cardiac protection associated with ischemic preconditioning decreases with age, and while SIRT1 also decreases with age, one study suggested these factors are independent (Adam et al , 2013). The cardiac protection in long term caloric restriction also is associated with an increase in nuclear but not total SIRT1 (Shinmura et al , 2008).…”

Sirtuin regulation in aging and injury

“…Therefore, although intracellular Nampt is essential to the cardiac myocyte survival, exogenous Nampt could be detrimental demanding fine balance between its synthesis and secretion. Interestingly, the cardiac protection conferred by IPC deteriorates with age [244]. The lack of ischemic tolerance in aged hearts is mainly accounted for by a reduced SIRT1 expression and activity although one study has ruled out the role of SIRT1 [244].…”

“…Interestingly, the cardiac protection conferred by IPC deteriorates with age [244]. The lack of ischemic tolerance in aged hearts is mainly accounted for by a reduced SIRT1 expression and activity although one study has ruled out the role of SIRT1 [244]. …”