Oxidative stress-elicited myocardial apoptosis during reperfusion

https://doi.org/10.1016/j.coph.2003.10.010Get rights and content

Abstract

Myocardial apoptosis primarily triggered during reperfusion has been associated with cardiac dysfunction and extension of infarction. Although potential signaling pathways involved in triggering apoptosis remain to be clearly defined, an increasing number of experiments have implicated the generation of reactive oxygen species (ROS). Increased levels of ROS have been shown to cause inflammatory and endothelial cell–cell interactions and calcium overload, resulting in enhanced release of pro-apoptotic genes from mitochondria. ROS also activate mitogen-activated protein kinases, stimulate nuclear factor-κB and promote synthesis of tumour necrosis factor-α. Attenuation of apoptosis by antioxidants has opened a new therapeutic window in the treatment of ischemia/reperfusion injury.

Introduction

Reperfusion after ischemia induces a sequence of events ultimately leading to cellular damage and organ dysfunction. By definition, reperfusion injury begins after the restoration of oxygen and metabolic substrates to energy-deprived and metabolically perturbed tissue. On the basis of experimental studies and clinical observations, significant progress in the understanding of pathological changes of reperfusion injury in the myocardium has been made during the past two decades. These alterations are not expressed during ischemia and can be modulated by interventions given only at the onset of reperfusion 1.••, 2., 3.. Apoptosis — a unique form of gene-regulated cell death — has been confirmed in myocardium after ischemia/reperfusion. Abundant evidence has demonstrated that apoptosis is primarily triggered or accelerated during reperfusion following a brief period of ischemia 4.•, 5.••. Our recent data have shown that the apoptosis in cells of the peri-necrotic zone of ischemic myocardium progressively developed over time following reperfusion [6], and an anti-apoptotic death therapy applied only at reperfusion reduced extension of infarction by inhibiting apoptosis [7]. Mechanisms involved in triggering apoptosis during reperfusion are not known in detail, but it is generally believed that the release and/or activation of various bioactive substances such as reactive oxygen species (ROS) [5••], chemotactic cytokines [1••] and complement [8] is responsible for the processes involved in induction of apoptosis during reperfusion. This review summarizes recent data showing the role of apoptosis in development of myocardial injury during reperfusion and the biochemical mechanisms involved in modulating apoptosis, with a special reference to oxidative stress-elicited signaling pathways. Potential future directions in the prevention of apoptosis using antioxidant therapy to reduce myocardial ischemia/reperfusion injury are also discussed.

Section snippets

Time course and features of cell death during ischemia and reperfusion

Differences in morphological and biochemical characteristics between the two distinct types of cell death in myocardium — necrosis and apoptosis — have been extensively reviewed elsewhere 9., 10., 11.. Briefly, necrosis — a rapidly formed pathological cell death — is primarily manifested either by cell swelling or by rupture of the plasma membrane and breakdown of cell organelles with a consequent significant inflammatory response. In contrast, apoptosis — a genetically controlled and

ROS generation and their cellular sources during reperfusion

ROS — consisting of superoxide anion, hydrogen peroxide and hydroxyl radical — have long been implicated as a major initiator of myocardial injury during reperfusion on the basis of the following findings: firstly, ROS are rapidly detected in the ischemic myocardium during the first minutes after reperfusion [21]; secondly, experimental application of ROS equivalents causes alterations in the myocardium that are similar to those resulting from reperfusion [22]; and finally, treatment with

Involvement of ROS in induction of myocardial apoptosis and potential signaling pathways

Although a conclusive role for ROS in induction of apoptosis and the associated signaling pathways is still under investigation, increasing evidence has suggested that ROS is a major contributor in triggering myocardial apoptosis 28., 29., 30.. Treatment with antioxidant agents significantly reduced the frequency of induction of myocardial apoptosis after ischemia/reperfusion [28]. Exposure of cultured rat cardiomyocytes to lower doses of an exogenous ROS-generating system, such as hydrogen

Attenuation of apoptosis by antioxidant therapy

From the foregoing discussion, it is clear that ROS is a major initiator of apoptosis. The appearance of myocardial apoptosis mediated by ROS during reperfusion has been associated with cardiac dysfunction and extension of infarction; blockade of this process can slow or even avoid the occurrence of these abnormalities. Previous studies with antioxidants and free radical scavengers have shown an inhibition of myocardial apoptosis. In in vivo canine and rat isolated models of regional and global

Conclusions

Although the role of apoptosis in the final extent of myocardial injury after ischemia/reperfusion is not completely understood, tremendous progress has been made in demonstrating that apoptosis developed during reperfusion significantly contributes both to myocardial morphological injury and to cardiac and endothelial dysfunction. The hypothesis that ROS are involved in induction of apoptosis has been supported by several experimental studies. It is now becoming clear that ROS generated during

Update

The role of ROS in induction of cell death and associated signaling pathways has been confirmed recently in simulated ischemia and reperfusion of HL-5 cardiac atrial myocyte cell lines [52]. ROS-triggered apoptosis occurred primarily during reperfusion. Blockade of p38, but not AKT and ERK, during reperfusion significantly protected cells from apoptotic death, and was accompanied by enhanced expression of anti-apoptotic Bcl-2 protein. Conversely, blockade of JNK activity resulted in a

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

This work was supported by grants from the National Institute of Health (HL64886) and from the Carlyle Fraser Heart Center of Emory University School of Medicine.

References (53)

  • S Verma et al.

    Fundamentals of reperfusion injury for the clinical cardiologist

    Circulation

    (2002)
  • Q.-D Wang et al.

    Pharmacological possibilities for protection against myocardial reperfusion injury

    Cardiovasc Res.

    (2002)
  • N Marczin et al.

    Redox regulation following cardiac ischemia and reperfusion

    Coron Artery Dis.

    (2003)
  • T.L Vanden Hoek et al.

    Reperfusion, not simulated ischemia, initiates intrinsic apoptosis injury in chick cardiomyocytes

    Am. J. Physiol. Heart Circ. Physiol.

    (2003)
  • C Li et al.

    Reactive species mechanisms of cellular hypoxia-reoxygenation injury

    Am. J. Physiol. Cell. Physiol.

    (2002)
  • Z.-Q Zhao et al.

    Progressively developed myocardial apoptotic cell death during late phase of reperfusion

    Apoptosis

    (2001)
  • Z.-Q Zhao et al.

    Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion

    Cardiovasc Res.

    (2003)
  • B De Vries et al.

    Inhibition of complement factor C5 protects against renal ischemia-reperfusion injury: inhibition of late apoptosis and inflammation

    Transplantation

    (2003)
  • A Abbate et al.

    Pathophysiologic role of myocardial apoptosis in post-infarction left ventricular remodeling

    J. Cell. Physiol.

    (2002)
  • C Gill et al.

    Losing heart: the role of apoptosis in heart disease-a novel therapeutic target?

    FASEB J.

    (2002)
  • Z.-Q Zhao et al.

    Myocardial apoptosis and ischemic preconditioning. [Review]

    Cardiovasc Res.

    (2002)
  • V Borutaite et al.

    Mitochondria in apoptosis of ischemic heart

    FEBS Lett.

    (2003)
  • Y Morita et al.

    Superoxide during reperfusion contributes to caspase-8 expression and apoptosis after transient focal stroke

    Stroke

    (2001)
  • P.W Thimister et al.

    In vivo detection of cell death in the area at risk in acute myocardial infarction

    J. Nucl. Med.

    (2003)
  • T Scarabelli et al.

    Apoptosis of endothelial cells precedes myocyte cell apoptosis in ischemia/reperfusion injury

    Circulation

    (2001)
  • A Atlante et al.

    The apoptosis/necrosis transition in cerebellar granule cells depends on themutual relationship of the antioxidant and the proteolytic systems which regulate ROS production and cytochrome c release en route to death

    J. Neurochem.

    (2003)
  • Cited by (167)

    View all citing articles on Scopus
    View full text