The Ischemic Heart

Abstract

HomeCirculationVol. 116, No. 24The Ischemic Heart Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Ischemic HeartStarving to Stimulate the Adiponectin-AMPK Signaling Axis Jason R.B. Dyck, PhD Jason R.B. DyckJason R.B. Dyck From the Cardiovascular Research Group, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Search for more papers by this author Originally published11 Dec 2007https://doi.org/10.1161/CIRCULATIONAHA.107.742023Circulation. 2007;116:2779–2781Caloric restriction has emerged as an effective strategy for lengthening lifespan in a variety of species.1 In mammals, one mechanism for this phenomenon may be the prevention of detrimental age-related alterations in cellular function1 and presumably subsequent improvement in organ function. The effects of caloric restriction on the heart, at least in rats and mice, involve a number of changes in gene expression that are beneficial to the aged cardiomyocyte2 and/or protect the heart from ischemic injury.3 Although it is likely that all of the beneficial mediators of caloric restriction have not been identified, a number of proteins in the mammalian sirtuin family may play key roles in the regulation of health and longevity.4 In addition, recent evidence has suggested that alterations in whole-body energy metabolism contribute to the beneficial effects of caloric restriction.5 Indeed, caloric restriction in mammals leads to loss of adipose tissue and dramatically alters the action of this endocrine organ.6 As such, caloric restriction contributes to changes in adipose tissue–derived hormone (adipokine) secretion, which can govern whole-body metabolism.7 Furthermore, studies using isolated cardiac myocytes suggest that these adipokines may exert direct end-organ effects that are independent from alterations in whole-body metabolism.8–10 One adipokine that is significantly increased during caloric restriction is adiponectin.11 Previous work has shown that adiponectin exerts a host of protective effects on the cardiovascular system12 and as such may be an essential component mediating the effects of caloric restriction.Article p 2809The focus on adiponectin in the cardiovascular system has been due largely to the fact that in humans, circulating adiponectin levels are negatively correlated with increased body mass index.13 Because increased body mass index is associated with a number of obesity-linked disorders, including cardiovascular disease, the reduction in serum adiponectin levels may contribute to disease development.14 On the basis of this rationale, adiponectin has been proposed to be beneficial in promoting cardiovascular health, and as such, its loss may contribute to the higher incidence of cardiovascular disease in obese individuals.12 Indeed, the beneficial effects of adiponectin on the cardiovascular system are quite extensive. In the vasculature, increased serum adiponectin levels assist in maintaining vascular tone via the stimulation of nitric oxide production in endothelial cells, promote angiogenesis after ischemic injury, protect against the formation of atherosclerotic lesions, and reduce smooth muscle cell growth and neointimal thickening in vascular lesions.12 In cardiac tissue, increased serum adiponectin lessens the development of concentric hypertrophy in a mouse model of aortic constriction10 and protects against ischemia/reperfusion injury in mice subjected to coronary artery ligation.9 The effects described in cardiac muscle are mediated, at least in part, by the activation of AMP-activated protein kinase (AMPK). Although AMPK activation by itself appears to inhibit hypertrophic growth in the cardiac myocyte,10,15 the protective effects of adiponectin during and after ischemia appear to be more complex and involve additional signaling pathways. Specifically, it has been shown previously that one of these auxiliary pathways may be the activation of cyclooxygenase-2, which also can protect the ischemic myocardium via a number of mechanisms.9 Although the evidence for the cardioprotective effects of adiponectin during ischemia is strong, it is still unclear whether AMPK is the central mediator of this effect.In a study published in this issue of Circulation, Shinmura et al16 demonstrate the cardioprotective effects of short-term caloric restriction on isolated mouse hearts subjected to ischemia/reperfusion. This study provides evidence that short-term caloric restriction (10% reduction in normal caloric intake for 3 weeks followed by a 35% reduction for 2 weeks) significantly increases serum adiponectin levels before ischemia, which results in improved left ventricular function throughout reperfusion. Furthermore, the authors demonstrate that short-term caloric restriction reduces infarct size from 28% of the left ventricular in ad libitum–fed mice to ≈19% in calorie-restricted mice. Evidence suggesting that adiponectin is the key signaling molecule under these conditions is provided through the use of transgenic mice expressing an antisense adiponectin oligonucleotide. In these mice, serum adiponectin levels are close to baseline values of the ad libitum–fed wild-type mice and are not elevated during caloric restriction. Consistent with the author’s hypothesis, the cardioprotective effects of caloric restriction are completely lost, and left ventricular function and infarct size are virtually indistinguishable in the ad libitum–fed transgenic mice compared with the calorie-restricted transgenic mice. Additionally, when recombinant adiponectin is administered to the transgenic mice in vivo, the beneficial effects of caloric restriction are restored. Taken together, these findings strongly implicate adiponectin as being responsible for mediating the cardioprotective effects of short-term caloric restriction.To explore the molecular mechanisms responsible for the beneficial effects of short-term caloric restriction and elevated serum adiponectin levels on the ischemic heart, the authors investigated AMPK phosphorylation status in hearts from calorie-restricted mice. In agreement with previous reports that adiponectin activates AMPK in the mouse heart,9,10 the 84% increase in serum adiponectin induced by short-term caloric restriction correlates with a significant increase in AMPK phosphorylation at its activation site. Subsequent administration of adenosine 9-D arabinofuranoside, a relatively nonspecific inhibitor of AMPK, to short-term calorie-restricted wild-type mice prevented both AMPK activation and the cardioprotective effects normally induced by short-term caloric restriction. On the basis of the evidence that the cardioprotective effect of short-term caloric restriction is mediated via the activation of AMPK, the authors propose that these effects form the basis of a novel form of preconditioning. That is, caloric restriction elevates serum adiponectin levels, which activates AMPK and subsequently preconditions the heart to better withstand a more severe ischemic insult. As such, Shinmura et al suggest that this mechanism may allow novel strategies aimed at stimulating the adiponectin-AMPK signaling axis to be developed for future use in ischemic heart disease and/or after acute myocardial infarction.Although the study by Shinmura et al provides valuable insights into the effects of short-term caloric restriction on the heart, a number of questions are yet to be answered. For example, if adiponectin is the sole signaling molecule responsible for the cardioprotective effects of caloric restriction, it remains to be resolved why the cyclooxygenase-2 pathway was not activated in this study as was shown previously.9 Whether this is related to the different models of ischemia/reperfusion is currently unknown. Indeed, the present study was performed using ex vivo perfused mouse hearts subjected to ischemia/reperfusion, whereas the previous study was performed in vivo.9 As such, additional factors contributing to ischemic injury in vivo may explain the differential effects of adiponectin signaling on the cyclooxygenase-2 pathway. Although the differential effects on the cyclooxygenase-2 pathway are yet to be resolved, the data presented by Shinmura et al are consistent with previous reports indicating that AMPK activation is a necessary component of the signal transduction pathway responsible for the cardioprotective effects induced by elevated serum adiponectin.9 However, given the use of the nonspecific inhibitor of AMPK in this study (ie, adenosine 9-D arabinofuranoside), there may be alterations in a number of AMPK-independent kinase signaling cascades, and it remains to be clarified whether the cardioprotective effects of adiponectin observed in this study can be attributed directly to AMPK activation or some other pathway. For example, although Shibata et al9 have shown that the addition of adiponectin during ischemia is cardioprotective, given the fact that severe ischemia likely maximally activates AMPK, the addition of adiponectin during ischemia may exert its cardioprotective effects via alternative signaling pathways. Whether this also is possible in the short-term caloric restriction model described by Shinmura et al remains to be elucidated.The above-mentioned comments notwithstanding, if AMPK is confirmed as the central mediator of the effects of adiponectin, the subsequent downstream effector pathways that protect the myocyte from ischemic damage remain to be elucidated. For example, it is unknown whether AMPK directly alters cell survival pathways to promote myocyte survival after ischemia or whether the protective effects of AMPK activation are purely metabolic in nature. To date, much of the research into the mechanisms by which AMPK activation protects the ischemic myocardium demonstrates reduced apoptosis,9,17 suggesting a direct link between AMPK and cellular survival pathways. However, it is also possible that vasodilatation induced by phosphorylation and activation of endothelial nitric oxide synthase by AMPK18 may lessen the severity of ischemia and enhance left ventricular function after ischemia. In addition, because AMPK is a pivotal regulator of energy homeostasis at both the cellular and whole-body levels,19 activation of AMPK by caloric restriction may profoundly alter myocardial energy metabolism.20,21 Although not fully explored, evidence presented by Shinmura et al suggests that cardiac energy metabolism may be involved. For instance, hearts from transgenic mice lacking the ability to increase serum adiponectin levels have a significant reduction in myocardial glycogen content when subjected to caloric restriction. Because glycogen becomes the primary source of myocardial ATP during no-flow ischemia, depleted glycogen stores before ischemia may be sufficient to adversely affect functional recovery after ischemia.22 This finding may partially explain the loss of protection induced by caloric restriction in these transgenic mice. Because myocardial glycogen levels and ATP levels immediately after ischemia were not reported, it is not known whether these hearts are more energetically compromised than hearts from calorie-restricted mice after ischemia. In addition, because glycogen levels were not determined in any other groups of hearts, it will be important to determine whether administration of recombinant adiponectin increases myocardial glycogen levels in the transgenic mice. This would provide insight into the role of glycogen in the cardioprotective effects of short-term caloric restriction and would help to determine whether alterations in cardiac energy metabolism play a role in this process.An additional concept underlying the study of Shinmura et al is that the activation of cardiac AMPK before ischemia is cardioprotective. However, it has yet to be definitively proven whether acute ischemia-induced activation of AMPK is beneficial or detrimental to the heart during reperfusion.20,21 Although it is recognized that activation of myocardial AMPK either before or during ischemia may have a beneficial effect of increased energy supply to the heart by stimulating glucose uptake, glycogenolysis, and glycolysis, it also may be detrimental to the heart after reperfusion by promoting fatty acid oxidation and subsequently decreasing cardiac efficiency.20,21 Because the concentration of fatty acids in the perfusate of ex vivo perfused hearts may profoundly alter functional recovery after ischemia,23 clinically relevant concentrations of fatty acids (ie, >1 mmol/L24) must be present in the perfusate to adequately address whether AMPK activation is detrimental or beneficial to the ischemic heart on reperfusion. Therefore, on the basis of this limitation of the study by Shinmura et al, it is still unknown whether short-term caloric restriction and subsequent activation of AMPK are beneficial in models of ischemia/reperfusion injury that include clinically relevant concentrations of fatty acids. That being said, the present study and the work by Shibata et al9 do suggest that activation of AMPK at least before an ischemic insult is cardioprotective. Although more work is needed to definitively prove this suggestion, if it turns out to be true, caloric restriction–induced elevations of serum adiponectin and subsequent activation of AMPK may indeed represent a novel method of ischemic preconditioning.In summary, the beneficial effects of long-term caloric restriction on longevity have become an exciting area of research1 and have the potential for significant clinical importance. Unfortunately, long-term caloric restriction in humans requires considerable patient discipline and is not likely sustainable despite potential health benefits. Therefore, short-term caloric restriction may be a more realistic approach. If short-term caloric restriction is achievable, the study by Shinmura et al highlights its potential cardiovascular benefits, specifically suggesting that this strategy may precondition the heart to better withstand a more severe ischemic insult. Interestingly, the studies performed by Shinmura et al involved nonobese mice, suggesting that adiponectin-mediated signaling is not maximally stimulated even when serum adiponectin levels are within the normal range. As such, stimulating the adiponectin-AMPK signaling axis either by caloric restriction or by pharmacological agents may be an effective therapeutic strategy applicable to a broad spectrum of patients, especially those with progressive ischemic heart disease at high risk for developing acute myocardial infarction, even in the absence of obesity.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Sources of FundingDr Dyck is supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Diabetes Association, and the Alberta Heritage Foundation for Medical Research (AHFMR) and is an AHFMR Senior Scholar and a Canada Research Chair in Molecular Biology of Heart Disease and Metabolism.DisclosuresNone.FootnotesCorrespondence to Jason R.B. Dyck, 474 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2. 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December 11, 2007Vol 116, Issue 24 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.107.742023PMID: 18071087 Originally publishedDecember 11, 2007 KeywordsdietischemiametabolismEditorialsadiponectinAMP-activated protein kinasePDF download Advertisement SubjectsAnimal Models of Human DiseaseMyocardial Infarction