Reactive Oxygen Species–Induced Stimulation of 5′AMP-Activated Protein Kinase Mediates Sevoflurane-Induced Cardioprotection

Abstract

Background-5ЈAMP-activated protein kinase (AMPK), a well-known regulator of cellular energy status, is also implicated in ischemic preconditioning leading to cardioprotection. We hypothesized that AMPK is involved in anesthetic-induced cardioprotection and that this activation is mediated by reactive oxygen species (ROS). Methods and Results-Isolated Langendorff-perfused rat hearts were subjected to 35 minutes of global ischemia (I) followed by 120 minutes of reperfusion (I/R). Hearts were assigned to a control group (Con) or a sevoflurane (Sevo) group receiving 3 times 5-minute episodes of sevoflurane (2.5vol%) before I/R. Phosphorylation of both AMPK and endothelial nitric oxide synthase (eNOS) were determined by Western blot analysis. Cardioprotection was assessed after I/R from recovery of left ventricular pressure and from infarct size (triphenyltetrazolium chloride staining). In the control group, ischemia resulted in a 2-fold increase in phosphorylation levels of AMPK (Con 0.13Ϯ0.01 versus Con-I 0.28Ϯ0.05, PϽ0.05), which was sustained after 120 minutes of reperfusion (Con-I/R 0.26Ϯ0.02, PϽ0.05). Sevoflurane preconditioning had no affect on AMPK phosphorylation before ischemia (Sevo 0.12Ϯ0.03, PϾ0.05), but almost doubled the increase in AMPK phosphorylation relative to control after ischemia (Sevo-I 0.48Ϯ0.09, PϽ0.05), an effect that was sustained after reperfusion (Sevo-I/R 0.49Ϯ0.12, PϽ0.05). The AMPK-inhibitor compound C (10 mol/L) reduced the sevoflurane-mediated increase in phosphorylation of AMPK and its target eNOS and abolished cardioprotection. The ROS-scavenger n-(2-mercaptopropionyl)-glycine (1 mmol/L) blunted the sevoflurane-mediated increase in AMPK and eNOS phosphorylation and prevented cardioprotection. Conclusions-Sevoflurane-induced AMPK activation protects the heart against ischemia and reperfusion injury and relies on upstream production of ROS. (Circulation. 2009;120[suppl 1]:S10-S15.)

Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats

“…Studies have shown that volatile anesthetics reduce myocardial damage in clinical practice and experimental research [3] . Previous studies on sevoflurane postconditioning (SpostC) have furthered the understanding of the role of anesthetic postconditioning in cardioprotection [4] ; however, the exact mechanisms responsible for the effects of SpostC are unclear.…”

“…Sevoflurane activates several pro-survival kinases, including protein kinase B (Akt) [5] , extracellular signal-regulated kinase (ERK) 1/2 [6] , and AMP-activated protein kinase (AMPK) [4] . These signals participate in regulating autophagy [7,8] .…”

Sevoflurane induces cardioprotection through reactive oxygen species-mediated upregulation of autophagy in isolated guinea pig hearts

“…However, the ex vivo conditions of the present study were designed to exclude possible confounding systemic hemodynamic and humoral effects of sevoflurane. Although we did not directly measure ROS during sevoflurane exposure, the dose (1 mM) of MPG used in the present study has been shown to abolish the infarct size limiting effect of sevoflurane preconditioning [10].…”

“…Novalija et al demonstrated that APC by sevoflurane is initiated by reactive oxygen species (ROS) produced during sevoflurane exposure and reduces the burst formation of ROS after ischemia-reperfusion in isolated guinea pig hearts [9]. Recently, cardioprotection by sevoflurane has been shown to be mediated by ROS-induced 5' AMP-activated protein kinase (AMPK) activation which is a well known regulator of cellular energy status [10].…”

Cardioprotective Effects Induced by Preconditioning with Halogenated Anesthetics

“…[16][17][18][19][20] This refers to the fact that short periods of ischemia, with a duration small enough not to produce cardiomyocyte necrosis, alternated with reperfusion, offers myocardial protection against an infarction produced by an ulterior prolonged ischemia, called in the specialized literature ischemia "test" or ischemia "index". 2,11,[21][22][23][24][25] In this paper, we present a study regarding the effects of two volatile anesthetic agents, Isoflurane and Sevoflurane on the heart, in situ, by using laboratory animals in which brain death was induced. This paper also presents the molecular mechanisms involved in the phenomenon of cardioprotection induced by volatile anesthetics in the brain-dead organ donor.…”