Letter by Lotz et al Regarding Article, “Reactive Oxygen Species–Induced Stimulation of 5′ AMP-Activated Protein Kinase Mediates Sevoflurane-Induced Cardioprotection”
To the Editor:
AMP kinase (AMPK) activation represents a unique molecular event in cardioprotection against ischemia/reperfusion injury, potentially linking myocardial metabolism to a number of cardioprotective signaling pathways such as nitric oxide and reactive oxygen species signaling. In a recently published article in Circulation, Lamberts et al1 demonstrated that AMPK activation contributed to the signaling cascade in the powerful cardioprotection conferred by sevoflurane-induced preconditioning. This finding is intriguing because AMPK activation has the potential to overcome the loss of anesthetic-induced preconditioning during diabetes mellitus.2 The published report provides important information and useful insights, particularly regarding the triangle of AMPK signaling, reactive oxygen species generation, and nitric oxide production during anesthetic-induced preconditioning. However, in our opinion, limitations in the experimental design may lead to misleading conclusions and seem to have prematurely determined AMPK activation as a favorable event.
In the study by Lamberts et al, compound C was used as a pharmacological antagonist of AMPK in an ex vivo model of isolated Langendorff-perfused rat hearts. Immunoblotting was utilized to characterize the role of AMPK activation during ischemic injury and protection. The data presented using compound C as an antagonist of AMPK seem to be controversial and somewhat inconclusive. Compound C may be a questionable antagonist of AMPK because compound C has been observed to exert cardiotoxic effects in a dosage not inhibiting AMPK activity in the in vivo model of ischemic injury.3 Furthermore, in the study by Lamberts et al, compound C given alone significantly decreased the resulting infarct size, an effect similar to the combined application of sevoflurane and compound C, weakening the authors’ conclusion that AMPK activation is beneficial and necessary for cardioprotection during anesthetic-induced preconditioning. Moreover, Lamberts et al found a 2-fold increase in AMPK phosphorylation after ischemia/reperfusion alone, whereas the addition of sevoflurane provoked a 4-fold increase, indicating that a robust activation of AMPK occurred in both groups. These data appear to contradict the claim that compound C suppressed AMPK and resulted in a reduced infarct size. Moreover, a recent investigation documented that suppression of cardiac AMPK activity did not produce an energetically compromised phenotype but rather improved myocardial function after ischemic injury,4 further arguing against the hypothesis that the cardioprotective effects of sevoflurane are indeed attributable only to AMPK activation. Differences in the experimental models used may account for the different results obtained; however, a clinically relevant in vivo model seems preferable over ex vivo conditions, especially considering the effects of AMPK on insulin signaling, certainly being able to alter the cardioprotective response.5 We are very interested in gaining insights from the authors on how to resolve these somewhat contradictory findings.
In summary, our view is that the jury is still out regarding whether AMPK activation benefits or harms the ischemic heart. Lamberts et al are to be congratulated for bringing AMPK signaling into focus; their study further underscores the importance of a more comprehensive characterization of AMPK signaling in the time course of ischemic injury in vivo. A multidisciplinary approach combining genetic models with metabolomic and proteomic techniques may offer a comprehensive approach to shed new light on the functional consequences of AMPK activation, acting either as an ally or an enemy of cardioprotection.
Lamberts RR, Onderwater G, Hamdani N, Vreden MJ, Steenhuisen J, Eringa EC, Loer SA, Stienen GJ, Bouwman RA. Reactive oxygen species-induced stimulation of 5′ AMP-activated protein kinase mediates sevoflurane-induced cardioprotection. Circulation. 2009; 120: S10–S15.
Tanaka K, Kehl F, Gu W, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR. Isoflurane-induced preconditioning is attenuated by diabetes. Am J Physiol Heart Circ Physiol. 2002; 282: H2018–H2023.
Folmes CD, Wagg CS, Shen M, Clanachan AS, Tian R, Lopaschuk GD. Suppression of 5′-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts. Am J Physiol Heart Circ Physiol. 2009; 297: H313–H321.
Jaswal JS, Gandhi M, Finegan BA, Dyck JR, Clanachan AS. Inhibition of p38 MAPK and AMPK restores adenosine-induced cardioprotection in hearts stressed by antecedent ischemia by altering glucose utilization. Am J Physiol Heart Circ Physiol. 2007; 293: H1107–H1114.