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AMPK and TNF-α at the crossroad of cell survival and death in ischaemic heart

Wei Peng, Yan Zhang, Weizhong Zhu, Chun-Mei Cao, Rui-Ping Xiao
DOI: http://dx.doi.org/10.1093/cvr/cvp272 1-3 First published online: 11 August 2009

Coronary atherosclerosis leads to ischaemic heart disease, the single greatest cause of death in developed countries. In the ischaemic heart, blockage of coronary circulation causes myocardial infarction (MI) which produces two types of damage: initial ischaemic injury and reperfusion injury following restoration of blood flow. Ischaemia–reperfusion (IR) injury leads to cardiac contractile dysfunction, loss of cardiomyocytes, maladaptive remodelling, and eventually congestive heart failure. Since mammalian cardiomyocytes are terminally differentiated cells with limited regenerative capacity, preservation of cardiomyocytes is an area that has attracted a lot of interest from both scientists and physicians. In this regard, studies by Kewalraman et al.1 have defined AMP-activated protein kinase (AMPK) as a powerful cardiac protector against tumour necrosis factor-alpha (TNF-α)-triggered cardiomyocyte apoptosis through phosphorylating Bad and subsequently suppressing mitochondrial apoptotic signalling. This discovery sheds new light on our understanding of the cardiac beneficial effects of clinically used hypoglycaemic drugs such as dexamethasone and metformin (MET), which activate AMPK and are widely used to treat type II diabetes. Equally important, this study may have important clinical relevance, since excessive TNF-α production has been implicated in the pathogenesis of a multitude of metabolic as well as cardiovascular disorders, including obesity, diabetes, and ischaemic heart disease. Thus, we envision that this work would stimulate a flurry of basic and translational studies in the field of cardiovascular biology and medicine and in the area of metabolic and inflammatory diseases.

Pathogenic role of TNF-α in the development of ischaemic heart disease

TNF-α is a proinflammatory cytokine expressed in almost all cells as an important intrinsic cellular stress response system to injury. Under normal conditions, stimulation of cells with TNF-α regulates multiple biological processes, including immune response, cell proliferation, dedifferentiation, and metabolism, thereby contributing to regional tissue homeostasis and local host defence responses.2 But under pathological conditions, exaggerated TNF-α production may cause devastating responses, including metabolic wasting (cachexia), microvascular coagulation, and lethal haemodynamic collapse.3 In particular, excessive TNF-α stimulation induces apoptosis mainly by the extrinsic pathway which sequentially involves the formation of a death-inducing signalling complex, activation of caspase-8, mitochondrial cytochrome c release, and activation of downstream caspase cascade, and eventually leading to apoptosis in fibroblasts, vascular smooth muscle cells, endothelial cells, and cardiomyocytes. Interestingly, TNF-α also triggers robust necrosis via promoting the formation of RIP1–RIP3 complex in certain cells.4,5

As to the heart, elevation of TNF-α has been implicated in the pathogenesis of IR injury, heart failure, and cardiac dysfunction seen during sepsis, shock, or myocarditis and after heart transplantation.6,7 In particular, production of TNF-α is markedly increased in response to IM and IR injury,7,8 and plays a major role in IM- and IR-induced myocardial damage and apoptosis.9,10 It is also noteworthy that TNF-α can trigger necrosis and induces infiltration of inflammatory cells which, in turn, provoke a sustained elevation of this proinflammatory cytokine and a vicious proinflammatory cycle at ischaemic myocardium, thus resulting in the severe myocyte loss and the progressive cardiac damage and maladaptive remodelling.

Yin-and-Yang balance between TNF-α and AMPK dictates fate of myocytes in ischaemic heart

Then, a question of life and death is how to cope with the loss of myocytes caused by sustained elevation of TNF-α and the vicious proinflammatory cycle in the ischaemic heart. In this regard, the study by Kewalramani et al.1 has demonstrated that activation of AMPK, a stress-responsive kinase, markedly inhibits TNF-α-induced cardiomyocyte apoptosis. The protective effect is attributable to AMPK-dependent phosphorylation of Bad and subsequent suppression of its interaction with Bcl-xL, thereby retaining the anti-apoptotic function of Bcl-xL and blocking mitochondrial apoptotic signalling events.1 Because MI or IR injury concurrently elevates TNF-α production and AMPK activation (Figure 1), this newly identified cardiac survival pathway may bear important pathogenic and therapeutic implications.

Figure 1

Schematic presentation shows myocardial infarction (MI) or ischaemia–reperfusion (IR) injury-induced concurrent increases in TNF-α production and AMPK activation with the former apoptotic and the latter protective in ischaemic heart. It awaits future investigation to determine whether AMPK activation suppresses TNF-α induced myocardial necrosis.

Consistent with the study by Kewalramani et al., it has been shown that adiponectin suppresses hypoxia-reoxygenation triggered apoptosis in cardiac myocytes and fibroblasts through AMPK-dependent mechanism.8 Likewise, AMPK activation protects H9c2 rat cardiac muscle cells and cultured cardiomyocytes against oxidative stress-induced apoptosis11,12 and prevents the progression of heart failure in a canine heart failure model.12 The anti-apoptotic effect of AMPK is also manifested by the fact that transgenic mice expressing a kinase-dead mutant of AMPK exhibit acerbated apoptosis and cardiac dysfunction after IR injury.13 Besides, emerging evidence suggests that AMPK activation by MET inhibits myocardial necrosis.14

In addition to its anti-apoptotic effect, AMPK is a master regulator of energy metabolism in the heart,15 as is the case for almost all cells, and activated during metabolic stress. Indeed, AMPK is rapidly and abundantly activated during ischaemia in isolated perfused rat hearts, which accounts for the acceleration of fatty acid oxidation in the post-ischaemic reperfused heart.16 Activated AMPK also stimulates glucose uptake in the ischaemic heart via inducing GLUT4 translocation from intracellular vesicles to the cell surface.17 Furthermore, AMPK phosphorylates and activates eukaryotic elongation factor-2 (eEF2) kinase, which inhibits cardiac protein synthesis, a major energy-consuming process. Additionally, AMPK may suppress cardiac pathological hypertrophy.18 Taken together, majority of studies has demonstrated that activation of AMPK increases energy production and suppresses apoptosis perhaps necrosis as well, thus protecting the heart against ischaemic stress.

In summary, the study by Kewalramani et al. has revealed a powerful cardioprotection by AMPK against TNF-α induced cardiac myocyte apoptosis. The anti-apoptotic effect of AMPK is mediated by increasing Bad phosphorylation and subsequently blocking mitochondrial apoptotic signalling events.1 These findings have not only revealed the molecular mechanism responsible for AMPK-mediated myocyte survival, but also defined Bad as a potential novel downstream AMPK target, marking AMPK as a potentially important therapeutic target for the treatment of ischemic and inflammatory heart diseases.

However, like all solid studies, this work has raised more questions than answers. First, is the significance of this work limited to ex vivo measurements in isolated cardiac myocytes? It merits future investigation to determine whether AMPK activation protects the heart against TNF-α-induced cardiotoxicity at the whole animal level. Secondly, how widely used is the currently described AMPK protective pathway? In other words, does AMPK activation protect non-cardiac organs such as brain and liver from TNF-α-induced cell injury and cell death? Finally, can AMPK inhibit TNF-α triggered necrotic cell death (Fig. 1)? Resolving these issues may provide new targets for clinical interventions and therapies to treat ischaemic heart disease in particular and metabolic disorders in general.

Funding

This work is supported by the Intramural Research Program of the NIH, National Institute on Aging (W.Z. and R.-P.X.) and, in part, by Peking University 985 Project (W.P., Y.Z., C.-M. C.).

Footnotes

  • The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology

References