Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1

Abstract

Ischemic tolerance decreases with aging, and the cardioprotective effect of ischemic preconditioning (IPC) is impaired in middle-aged animals. We have demonstrated that short-term caloric restriction (CR) improves myocardial ischemic tolerance in young and old animals via the activation of adiponectin-AMP-activated protein kinase (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 silent information regulator 1 (Sirt1; which reportedly mediates various aspects of the CR response) with prolonged CR. Thus, 6-mo-old male Fischer-344 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 120 min of reperfusion with or without IPC. CR improved the recovery of left ventricular function and reduced infarct size after ischemiareperfusion and restored the IPC effect. 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 CR; however, in the nuclear fraction, CR significantly increased Sirt1 and decreased acetyl-histone H3. Eleven rats from each group were given N-nitro-L-arginine methyl ester in their drinking water for 4 wk before death. In these hearts, chronic inhibition of nitric oxide synthase prevented the increase in nuclear Sirt1 content by CR and abrogated CR-induced cardioprotection. These results demonstrate that 1) prolonged CR improves myocardial ischemic tolerance and restores the IPC effect in middle-aged rats and 2) CR-induced cardioprotection is associated with a nitric oxidedependent increase in nuclear Sirt1 content. aging; myocardial ischemia; nutrition; preconditioning; reperfusion injury; silent information regulator 1

Role of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection

“…Murry and colleagues (51) were the first to demonstrate the preconditioning phenomenon, which typically refers to the observation that short, discontinuous episodes (i.e., one or more) of ischemia protects tissue against a subsequent prolonged period of ischemia. Importantly, ischemia is not the only stimulus that can precondition tissue, since there is now evidence to suggest that pharmacological agents (15,67) and interventions such as caloric restriction (62) and exercise (17, 44) also mimic the protective effects of brief ischemic insults. Preconditioning consists of two distinct phases: the initial window of protection and the second window of protection.…”

Caloric restriction and heart function: is there a sensible link?

“…The cardioprotection induced by CR is associated with an increase in AMPK activation [66] . Furthermore prolonged CR (6 months) improves myocardial ischemic tolerance and restores ischemic preconditioning (IP) effect in middle-aged rats, possible through a nitric oxide-dependent increase in nuclear human silent information regulator type 1 (SIRT1) content [67] . CR also promoted ischemia-induced revascularization in wild-type mice but not adiponectin knockout mice.…”

“…CR also promoted ischemia-induced revascularization in wild-type mice but not adiponectin knockout mice. Adiponectin is known to promote vascular cell function and survival under stressed condi tions [66,67] . It was recently reported that CR may confer resistance to myocardial ischemia-reperfusion injury by increasing adiponectin levels [68] .…”

Sirtuins, aging, and cardiovascular risks

“…Unexpectedly, Shinmura et al (2008) found that myocardial levels of total SIRT1 protein did not change with caloric restriction.…”

“…Yamamoto et al (2014) observed that since caloric restriction, which protects the heart from ischemia/ reperfusion injury, failed to induce cardioprotection in SIRT1 knockout mice, the cardioprotective effect of caloric restriction is in part mediated through activation of the Nampt-SIRT1 pathway, in which Nampt plays a critical role as a regulator for NAD + synthesis in cardiomyocyte. SIRT1 confers cardioprotection and cytoprotective effects mainly by preventing apoptotic cell death (Alcendor et al 2004;Shinmura et al 2008). …”