Postischaemic reperfusion injury in the isolated rat heart: effect of ruthenium red

Figueredo, Vincent M.; Dresdner, K P; Wolney, Arlene C; Keller, Andrew

doi:10.1093/cvr/25.4.337

Cited by 49 publications

(26 citation statements)

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“…Of note, prior studies using MCU blockers have yielded divergent effects, protecting isolated mitochondria from hypoxic injury (Schild et al, 2003), but having either beneficial effects, or deleterious effects associated with cytosolic Ca 2+ overload in both neuronal and cardiac tissues depending upon the precise paradigm employed (Figueredo et al, 1991; Ruiz-Meana et al, 2006; Velasco and Tapia, 2000; Zhao et al, 2013). In line with these observations, we find that addition of RR during OGD carried out in physiological [Ca 2+ ] e in the absence of Ca 2+ entry blockers accelerated the Ca 2+ deregulation (Figure 1B), likely by interfering with the ability of mitochondria to buffer large cytosolic Ca 2+ loads, and possibly obscuring the ability to resolve beneficial effects of blocking mitochondrial Zn 2+ entry.…”

Section: Discussionmentioning

confidence: 99%

Intramitochondrial Zn2+ accumulation via the Ca2+ uniporter contributes to acute ischemic neurodegeneration

Medvedeva

Weiss

2014

Neurobiology of Disease

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Ca2+ and Zn2+ have both been implicated in the induction of acute ischemic neurodegeneration. We recently examined changes in intracellular Zn2+ and Ca2+ in CA1 pyramidal neurons subjected to oxygen glucose deprivation (OGD), and found that Zn2+ rises precede and contribute to the onset of terminal Ca2+ rises (“Ca2+ deregulation”), which are causatively linked to a lethal loss of membrane integrity. The present study seeks to examine the specific role of intramitochondrial Zn2+ accumulation in ischemic injury, using blockers of the mitochondrial Ca2+ uniporter (MCU), through which both Zn2+ and Ca2+ appear able to enter the mitochondrial matrix. In physiological extracellular Ca2+, treatment with the MCU blocker, Ruthenium Red (RR), accelerated the Ca2+ deregulation, most likely by disrupting mitochondrial Ca2+ buffering and thus accelerating the lethal cytosolic Ca2+ overload. However, when intracellular Ca2+ overload was slowed, either by adding blockers of major Ca2+ entry channels or by lowering the concentration of Ca2+ in the extracellular buffer, Ca2+ deregulation was delayed, and under these conditions either Zn2+ chelation or MCU blockade resulted in similar further delays of the Ca2+ deregulation. In parallel studies using the reactive oxygen species (ROS) indicator, hydroethidine, lowering Ca2+ surprisingly accelerated OGD induced ROS generation, and in these low Ca2+ conditions, either Zn2+ chelation or MCU block slowed the ROS generation. These studies suggest that, during acute ischemia, Zn2+ entry into mitochondria via the MCU induces mitochondrial dysfunction (including ROS generation) that occurs upstream of, and contributes to the terminal Ca2+ deregulation.

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Section: Discussionmentioning

confidence: 99%

Intramitochondrial Zn2+ accumulation via the Ca2+ uniporter contributes to acute ischemic neurodegeneration

Medvedeva

Weiss

2014

Neurobiology of Disease

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“…Reducing cytosolic and mitochondrial Ca 2+ overload with antagonists of plasma membrane or mitochondrial Ca 2+ channels such as verapamil and Ruthenium Red has also been shown to protect hearts from reperfusion injury [204][205][206][207][208][209][210][211], but a direct demonstration that this involves inhibition of the MPTP has not been reported. A similar mechanism probably applies to the protection seen in hearts reperfused with elevated extracellular Mg 2+ concentration (>8 mM) [212][213][214].…”

Section: Reduced Ca 2+ Loading and Phmentioning

confidence: 99%

A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

Halestrap

2010

Biochemical Society Transactions

272

239

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In addition to their normal physiological role in ATP production and metabolism, mitochondria exhibit a dark side mediated by the opening of a non-specific pore in the inner mitochondrial membrane. This mitochondrial permeability transition pore (MPTP) causes the mitochondria to breakdown rather than synthesize ATP and, if unrestrained, leads to necrotic cell death. The MPTP is opened in response to Ca(2+) overload, especially when accompanied by oxidative stress, elevated phosphate concentration and adenine nucleotide depletion. These conditions are experienced by the heart and brain subjected to reperfusion after a period of ischaemia as may occur during treatment of a myocardial infarction or stroke and during heart surgery. In the present article, I review the properties, regulation and molecular composition of the MPTP. The evidence for the roles of CyP-D (cyclophilin D), the adenine nucleotide translocase and the phosphate carrier are summarized and other potential interactions with outer mitochondrial membrane proteins are discussed. I then review the evidence that MPTP opening mediates cardiac reperfusion injury and that MPTP inhibition is cardioprotective. Inhibition may involve direct pharmacological targeting of the MPTP, such as with cyclosporin A that binds to CyP-D, or indirect inhibition of MPTP opening such as with preconditioning protocols. These invoke complex signalling pathways to reduce oxidative stress and Ca(2+) load. MPTP inhibition also protects against congestive heart failure in hypertensive animal models. Thus the MPTP is a very promising pharmacological target for clinical practice, especially once more specific drugs are developed.

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“…Reperfusion injury, a paradoxical worsening of myocardial damage when circulation is restored to coronary arteries after prolonged ischemia, can increase infarct size and worsen outcome after myocardial infarction (11,12). Recent evidence in experimental animals indicates that ischemia-reperfusion injury can be reduced by preconditioning the heart with brief episodes of ischemia and reperfusion prior to prolonged ischemia (13)(14)(15)(16).…”

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confidence: 99%

Regular alcohol consumption mimics cardiac preconditioning by protecting against ischemia–reperfusion injury

Miyamae

Diamond

Weiner

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Epidemiologic studies indicate that longterm alcohol consumption decreases the incidence of coronary disease and may improve outcome after myocardial infarction. Attenuation of ischemia-reperfusion injury after myocardial infarction improves survival. This study investigates the possibility that alcohol consumption can improve survival after myocardial infarction by reducing ischemia-reperfusion injury. Hearts were isolated from guinea pigs after drinking ethanol for 3-12 weeks and subjected to global ischemia and reperfusion. Hearts from animals drinking ethanol showed improved functional recovery and decreased myocyte damage when compared with controls. Adenosine A 1 receptor blockade abolished the protection provided by ethanol consumption. These findings indicate that long-term alcohol consumption reduces myocardial ischemia-reperfusion injury and that adenosine A 1 receptors are required for this protective effect of ethanol. This cardioprotective effect of long-term alcohol consumption mimics preconditioning and may, in part, account for the beneficial effect of moderate drinking on cardiac health.

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Postischaemic reperfusion injury in the isolated rat heart: effect of ruthenium red

Abstract: Combined with the known inhibitory effect of ruthenium red on mitochondrial calcium uptake, these data suggest that an important component of myocardial injury following ischaemia and reperfusion in the isolated rat heart is the result of mitochondrial calcium accumulation.

Cited by 49 publications

References 0 publications

Intramitochondrial Zn2+ accumulation via the Ca2+ uniporter contributes to acute ischemic neurodegeneration

Intramitochondrial Zn2+ accumulation via the Ca2+ uniporter contributes to acute ischemic neurodegeneration

A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

Regular alcohol consumption mimics cardiac preconditioning by protecting against ischemia–reperfusion injury

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