Abstract 5425: Nuclear Shuttling of Sirt1 Is Associated with Caloric Restriction-Induced Cardioprotection

Abstract

Ischemic tolerance decreases with ageing and the cardioprotective effect of ischemic preconditioning (PC) is impaired in middle-aged animals. We have demonstrated that short-term caloric restriction (CR) improves myocardial ischemic tolerance via the activation of adiponectin-AMPK-mediated signaling. However, it is unknown whether prolonged CR confers cardioprotection in a similar manner. Furthermore, little is known regarding the myocardial expression of sirt1 (which reportedly mediates various aspects of the CR response) with ageing and prolonged CR. Thus, 6-month-old Fischer344 rats were randomly divided into ad libitum (AL) and CR groups. Six months later, isolated perfused hearts were subjected to 25 min of global ischemia followed by 30 min of reperfusion with or without ischemic PC. CR improved the recovery of LV developed pressure (A) and restored the cardioprotective effect of ischemic PC. Serum adiponectin levels increased but myocardial levels of total and phosphorylated AMPK did not change with prolonged CR. Total levels of sirt1 did not change with ageing and CR; however, in the nuclear fraction, CR significantly increased sirt1 (B) and decreased acetyl-histone H3. Eight rats from each group were given L-NAME in the drinking water for 4 weeks before sacrifice. In these hearts, chronic inhibition of nitric oxide (NO) synthase prevented the nuclear shuttling of sirt1 by CR (B) and abrogated CR-induced cardioprotection (A). These results demonstrate that prolonged CR improves myocardial ischemic tolerance and restores ischemic PC in middle-aged rats, and that CR-induced cardioprotection is associated with NO-dependent nuclear shuttling of sirt1.