Bidirectional regulation of Ca2+ sparks by mitochondria-derived reactive oxygen species in cardiac myocytes

Yuan, Yan; Liu, Jie; Wei, Chaoliang; Li, Kaitao; Xie, Wenjun; Wang, Yanru; Cheng, Heping

doi:10.1093/cvr/cvm047

Cited by 132 publications

(115 citation statements)

References 31 publications

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“…The FFA present in cells provides a perpetuating and propagating mechanism for oxidative stress via the process of lipid peroxidation and produces large amounts of ROS and free radicals that cause secondary damage to cellular membranes and key organelles, including the ER; additionally, the SERCAs in the membrane of the ER are highly sensitive to ROS (6,52). In our study, we observed distinct alterations in the cytosolic calcium homeostasis after the exposure of the hepatocytes to PA (Fig.…”

Section: Discussionsupporting

confidence: 50%

Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis

Zhang

Jiang

et al. 2014

American Journal of Physiology-Cell Physiology

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Section: Discussionsupporting

confidence: 50%

Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis

Zhang

Jiang

et al. 2014

American Journal of Physiology-Cell Physiology

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“…The RyR amino acid sequence immediately proximal to S2808 is RRIS, which implicates a PKA site and therefore a potentially important substrate for ␤-adrenergic signaling. Such exposure would furthermore leave RyR function particularly susceptible to oxidative stress, which is known to liberate protein-bound zinc (9,34) and also to enhance RyR open probability (37).…”

Section: Discussionmentioning

confidence: 99%

Identifying cellular mechanisms of zinc-induced relaxation in isolated cardiomyocytes

Vick

Vecchio

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Yi T, Vick JS, Vecchio MJ, Begin KJ, Bell SP, Delay RJ, Palmer BM. Identifying cellular mechanisms of zinc-induced relaxation in isolated cardiomyocytes. Am J Physiol Heart Circ Physiol 305: H706-H715, 2013. First published June 28, 2013 doi:10.1152/ajpheart.00025.2013.-We tested several molecular and cellular mechanisms of cardiomyocyte contraction-relaxation function that could account for the reduced systolic and enhanced diastolic function observed with exposure to extracellular Zn 2ϩ . Contraction-relaxation function was monitored in isolated rat and mouse cardiomyocytes maintained at 37°C, stimulated at 2 or 6 Hz, and exposed to 32 M Zn 2ϩ or vehicle. Intracellular Zn 2ϩ detected using FluoZin-3 rose to a concentration of ϳ13 nM in 3-5 min. Peak sarcomere shortening was significantly reduced and diastolic sarcomere length was elongated after Zn 2ϩ exposure. Peak intracellular Ca 2ϩ detected by Fura-2FF was reduced after Zn 2ϩ exposure. However, the rate of cytosolic Ca 2ϩ decline reflecting sarcoplasmic reticulum (SR) Ca 2ϩ -ATPase (SERCA2a) activity and the rate of Na ϩ /Ca 2ϩ exchanger activity evaluated by rapid Na ϩ -induced Ca 2ϩ efflux were unchanged by Zn 2ϩ exposure. SR Ca 2ϩ load evaluated by rapid caffeine exposure was reduced by ϳ50%, and L-type calcium channel inward current measured by whole cell patch clamp was reduced by ϳ70% in cardiomyocytes exposed to Zn 2ϩ . Furthermore, ryanodine receptor (RyR) S2808 and phospholamban (PLB) S16/T17 were markedly dephosphorylated after perfusing hearts with 50 M Zn 2ϩ . Maximum tension development and thinfilament Ca 2ϩ sensitivity in chemically skinned cardiac muscle strips were not affected by Zn 2ϩ exposure. These findings suggest that Zn 2ϩ suppresses cardiomyocyte systolic function and enhances relaxation function by lowering systolic and diastolic intracellular Ca 2ϩ concentrations due to a combination of competitive inhibition of Ca 2ϩ influx through the L-type calcium channel, reduction of SR Ca 2ϩ load resulting from phospholamban dephosphorylation, and lowered SR Ca 2ϩ leak via RyR dephosphorylation. The use of the low-Ca 2ϩ -affinity Fura-2FF likely prevented the detection of changes in diastolic Ca 2ϩ and SERCA2a function. Other strategies to detect diastolic Ca 2ϩ in the presence of Zn 2ϩ are essential for future work.cardiac; myocyte; sarcomere; L-type channel; ryanodine receptor THE IMPORTANCE of zinc and zinc ion (Zn 2ϩ ) in cardiac muscle function is only partially understood at this time. Cardiac zinc content correlates positively with ejection fraction (EF) in humans (18), and zinc supplementation to cardioplegic solution protects against the loss of systolic function and enhances diastolic function during and after ischemia-reperfusion injury (23-25). It has been suggested that zinc combats oxidative stress associated with ischemia-reperfusion and diabetes in part by enhancing the capacity of the zinc-binding protein metallothionein (15), which shields against reactive oxygen species (13, 23-25, 27, 36).Zinc deficiency (Ͻ10.7 M plasm...

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“…Increases in mitochondrial Ca 2+ concentration ([Ca 2+ ] m ) induce the opening of the mitochondrial permeability transition pore (MPTP) leading to inhibition of ATP synthesis, increased ROS production, cytochrome c release and cell death by apoptosis (6,7). Ruthenium red (RR) and Ru360 block the MCU to reduce the Ca 2+ influx and, therefore, exert a beneficial effect during I/R injury by preventing Ca 2+ accumulation (8).…”

Section: Introductionmentioning

confidence: 99%

The role of the mitochondrial calcium uniporter in cerebral ischemia/reperfusion injury in rats involves regulation of mitochondrial energy metabolism

Zhao

Wang

et al. 2013

Molecular Medicine Reports

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Abstract. The mitochondrial calcium uniporter (MCU) maintains intracellular Ca2+ homeostasis by transporting Ca 2+ from the cell cytosol into the mitochondrial matrix and is important for shaping Ca 2+ signals and the activation of programmed cell death. Inhibition of MCU by ruthenium red (RR) or Ru360 has previously been reported to protect against neuronal death. The aim of the present study was to analyze the mechanisms underlying the effects of MCU activity in a rat model of cerebral ischemia/reperfusion (I/R) injury. Adult male Wistar rats were divided into 4 groups; sham, I/R, I/R + RR and I/R + spermine (Sper) and were subjected to reversible middle cerebral artery occlusion for 2 h followed by 24 h of reperfusion. A bolus injection of RR administered 30 min prior to ischemia was found to significantly decrease the total infarct volume and reduce neuronal damage and cell apoptosis compared with ischemia/reperfusion values. However, treatment with Sper, an activator of the MCU, increased the injury induced by I/R. Analysis of energy metabolism revealed that I/R induced progressive inhibition of complexes I-IV of the electron transport chain, decreased ATP production, dissipated the mitochondrial membrane potential and increased the generation of reactive oxygen species. Treatment with RR ameliorated the condition, while spermine had the opposite effect. In conclusion, blocking MCU was demonstrated to exert protective effects against I/R injury and this process may be mediated by the prevention of energy failure.

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Bidirectional regulation of Ca2+ sparks by mitochondria-derived reactive oxygen species in cardiac myocytes

Cited by 132 publications

References 31 publications

Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis

Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis

Identifying cellular mechanisms of zinc-induced relaxation in isolated cardiomyocytes

The role of the mitochondrial calcium uniporter in cerebral ischemia/reperfusion injury in rats involves regulation of mitochondrial energy metabolism

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