Myocardial reperfusion: a double-edged sword?

Braunwald, Eugene; Kloner, Robert A.

doi:10.1172/jci112160

Cited by 1,231 publications

(598 citation statements)

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“…However, it can also paradoxically lead to cardiomyocyte injury and death. 14 One of the main actors of this lethal reperfusion injury is cellular Ca 2+ overload, 15 which results in part from excessive sarco/endoplasmic reticulum (SR/ER) Ca 2+ release and Ca 2+ influx through the plasma membrane (e.g. through L-type Ca 2+ channel and NCX (sodium-calcium exchanger)).…”

mentioning

confidence: 99%

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

Gomez¹,

Thiebaut²,

Paillard³

et al. 2015

Cell Death Differ

108

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Glycogen synthase kinase-3β (GSK3β) is a multifunctional kinase whose inhibition is known to limit myocardial ischemiareperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/ endoplasmic reticulum (SR/ER) are key players in cell death signaling. Their involvement in myocardial ischemia-reperfusion injury has gained recognition recently, but the underlying mechanisms are not yet well understood. We questioned here whether GSK3β might have a role in the Ca 2+ transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3β protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3β specifically interacted with the inositol 1,4,5-trisphosphate receptors (IP 3 Rs) Ca 2+ channeling complex in MAMs. We demonstrated that both pharmacological and genetic inhibition of GSK3β decreased protein interaction of IP 3 R with the Ca 2+ channeling complex, impaired SR/ER Ca 2+ release and reduced the histamine-stimulated Ca 2+ exchange between SR/ER and mitochondria in cardiomyocytes. During hypoxia reoxygenation, cell death is associated with an increase of GSK3β activity and IP 3 R phosphorylation, which leads to enhanced transfer of Ca 2+ from SR/ER to mitochondria. Inhibition of GSK3β at reperfusion reduced both IP 3 R phosphorylation and SR/ER Ca 2+ release, which consequently diminished both cytosolic and mitochondrial Ca 2+ concentrations, as well as sensitivity to apoptosis. We conclude that inhibition of GSK3β at reperfusion diminishes Ca 2+ leak from IP 3 R at MAMs in the heart, which limits both cytosolic and mitochondrial Ca 2+ overload and subsequent cell death. Glycogen synthase kinase-3 (GSK3) was originally identified as a phosphorylating kinase for glycogen synthase. 1,2 It has two isoforms, α and β, that possess strong homology in their kinase domains with, however, distinct functions. 3 GSK3 is constitutively active but it can be inhibited by phosphorylation on serine 21 (Ser21) for GSK3α and Ser9 for GSK3β. 4 In the heart, GSK3β has several important roles in cardiac hypertrophy 5 and ischemia-reperfusion (IR) injury. 6 Accumulating evidence indicates that phospho-Ser9-GSK3β-mediated cytoprotection is achieved by an increased threshold for permeability transition pore (PTP) opening. [6][7][8][9] The mechanism by which GSK3β delays PTP opening still remains unclear. It has been reported that GSK3β could interact with ANT at the inner mitochondrial membrane in the heart 9 and/or to phosphorylate voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) in cancer cells. 10,11 GSK3β also has other proposed mechanisms of action, including a poorly characterized role in calcium (Ca 2+ ) homeostasis regulation 12 and protein-protein interactions, 9 as well as functions in different subcellular fractions such as the nucleus, cytosol and mitochondria. 13 Reperfusion is the most powerful intervention to salvage ischemic myocardium. However, it can also paradoxically lead to ca...

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mentioning

confidence: 99%

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

Gomez¹,

Thiebaut²,

Paillard³

et al. 2015

Cell Death Differ

108

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“…31 Acute myocardial infarction is accompanied by activation of numerous systemic and local neurohumoral factors, including the renin-angiotensin system. 32,33 Furthermore, reperfusion of the acutely infarcted area (as obtained experimentally by removal of a coronary ligature and clinically by thrombolytic agents) produces a surge in reactive oxygen species, causing tissue damage beyond that inflicted by ischaemia 34 and partially attributed to activation of local humoral factors, including A II. Inhibition of ACE was shown to minimize the extent of this damage, 35,36 although it is unclear how much of this benefit should be attributed to A II suppression and how much to potentiation of bradykinin.…”

Section: Oxidative Stressmentioning

confidence: 99%

Angiotensin II as a cardiovascular risk factor

Gavras

2002

J Hum Hypertens

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A renin-angiotensin level that is inappropriately high for the systemic blood pressure and the state of sodium balance is now recognized to be one of the modifiable cardiovascular risk factors. Angiotensin acts both as a circulating hormone and as a locally acting paracrine/autocrine/intracrine factor. The adverse effects of angiotensin on the heart include the mechanical results of elevated resistance to the pumping function of the myocardium, as well as the effects of neurohumoral abnormalities on various cardiac structures. In addition, cardiac damage follows acute ischaemic injury or chronic energy starvation due to coronary artery disease, attributable to either mechanical obstruction Keywords: angiotensin II; renin-angiotensin system; cardiovascular disease; myocardial infarction Myocardial ischaemiaAngiotensin II (A II) is one of the major systemic pressor hormones (others include noradrenaline, vasopressin and endothelin). The idea that excessive levels of circulating A II can cause myocardial infarctions originated from an early experiment in which exogenous infusion of A II produced widespread areas of myocardial necrosis in rabbits. 1 Clinical observations in patients subjected to extreme stimulation of the renin-angiotensin system during haemodialysis revealed that these patients were prone to coronary death. This was attributed to intense coronary vasoconstriction, because focal myocardial necrosis was described in areas with no detectable coronary obstructive lesions. 2 These experiments were later replicated and amplified by other investigators. 3,4 It was found that an excess of endogenous or exogenous A II can damage the myocardium via several additional mechanisms, such as increased sarcolemmic permeability and death of cardiac myocytes, or increased permeability and destruction of coronary microvascular endothelial cells. All these eventually lead to the replacement of contractile myocardium by fibrotic tissue.Angiotensin II exerts a preferential pressor action on the coronary, renal, cerebral and adrenal vasculaCorrespondence: H Gavras, Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. E-mail: hgavrasȰbu.edu (atherosclerotic and/or thrombotic) or functional stenosis (vasospasm). Activation of the renin-angiotensin system has several haemodynamic and humoral consequences, all of which may damage the myocardium. These include acute myocardial ischaemia, left-ventricular hypertrophy, arrhythmias, alterations in the coagulation-fibrinolysis equilibrium, increased oxidative stress, and pro-inflammatory activity. A brief review of some of the mechanisms by which activation of the renin-angiotensin system can inflict damage on the heart is presented.

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Section: Overview Of Ischaemic Damage and Reperfusion Injurymentioning

confidence: 99%

“…This discovery led to the concept of 'reperfusion injury' (Braunwald and Kloner 1985). The paradox that reperfusion is both necessary for survival and damaging has lead to it being described as a 'doubleedged sword' (Braunwald and Kloner 1985). Reperfusion injury is an important consideration from a clinical perspective because whilst it is almost impossible to predict when cardiac arrest will occur, reperfusion can happen as a result of a medical intervention (e.g.…”

Section: Overview Of Ischaemic Damage and Reperfusion Injurymentioning

confidence: 99%