Inhibitors of SERCA and mitochondrial Ca-uniporter decrease velocity of calcium waves in rat cardiomyocytes

Landgraf, Grit; Gellerich, Frank N.; Wussling, M

doi:10.1023/b:mcbi.0000009883.71379.51

Cited by 18 publications

(7 citation statements)

References 40 publications

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“…Ruthenium red, at nano to micromolar concentrations, induces mitochondrial toxicity by disrupting the Ca 2+ uniporter, inactivating Ca 2+ ‐dependent mitochondrial enzymes and impairing complex I activity . Ruthenium compounds have demonstrated significant mitochondrial toxicity adding support to the hypothesis that the ruthenium base of CORM‐2 may be responsible for the impairment of complex I activity observed in this study.…”

Section: Discussionsupporting

confidence: 79%

Cell Damage Following Carbon Monoxide Releasing Molecule Exposure: Implications for Therapeutic Applications

Winburn

Gunatunga

McKernan

et al. 2012

Basic Clin Pharma Tox

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The cytoprotective properties of carbon monoxide (CO) gas and CO-releasing molecules (CORMs) are well established. Despite promising pre-clinical results, little attention has been paid to the toxicological profile of CORMs. The effects of CORM-2 and its CO-depleted molecule (iCORM-2) (20-400 lM) were compared in primary rat cardiomyocytes and two cell lines [human embryonic kidney (HeK) and Madine-Darby canine kidney Cells (MDCK)]. Cells were assessed for cell viability, apoptosis, necro-sis, cytology, mitochondrial energetics, oxidative stress and cell cycle arrest markers. In separate experiments, the anti-apoptotic effects of CORM-2 and i-CORM-2 treatment were compared against CO gas treatment in HeK and MDCK lines. H 2 O 2-induced cellular damage, measured by lactate dehydrogenase (LDH) release from primary cardiomyocytes, was reduced by 20 lM CORM-2; LDH activity, however, was directly inhibited by 400 lM CORM-2. Both CORM-2/iCORM-2 and CO gas decreased cisplatin-induced caspase-3 activity in MDCK and HeK cells suggesting an anti-apoptotic effect. Conversely, both CORM-2 and iCORM-2 induced significant cellular toxicity in the form of decreased cell viability, abnormal cell cytology, increased apoptosis and necrosis, cell cycle arrest and reduced mitochondrial enzyme activity. Comparison of these markers after CO gas administration to MDCK cells found significantly less cellular toxicity than in 100 lM CORM-2/iCORM-2-treated cells. CO gas did not have an adverse effect on mitochondrial energetics and integrity. Release of CO by low concentrations of intact CORM-2 molecules provides cyto-protective effects. These results show, however, that the ruthenium-based CORM by-product, iCORM-2, is cytotoxic and suggest that the accumulation of iCORM-2 would seriously limit any clinical application of the ruthenium-based CORMs. Carbon monoxide (CO), iron and biliverdin are products of the catabolism of haem by the enzyme haem oxygenase (HO) [1]. Both CO administration and HO-1 induction have been demonstrated to afford cytological and organ protection in a number of models [2,3]. CO provides cytoprotection via a number of different mechanisms that include anti-inflammatory [4], vasodilatory [5,6], anti-coagulative [7], anti-apoptotic [7,8] and anti-proliferative/fibrotic pathways [3]. The anti-apoptotic properties of CO have been demonstrated in both in vivo and in vitro models to involve modulation of intrinsic pathways, extrinsic pathways and also up-regulation of protective anti-apoptotic Bcl-X L /Bax interaction [6-9]. CO exerts a variety of effects on mitochondrial function dependent on its concentration, duration of exposure and cell type studied. Both endogenous and exogenous CO have been demonstrated to diminish cellular respiration via inhibition of complex IV [10,11]. However, inhibition of complex IV by CO may account in part for some of its cytoprotective effects, by creating a 'metabolic hypoxia' [12] and activating anti-inflammatory p38 MAPK pathways via ROS release [13]. Exposure of rats to CO (50 ppm;...

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Section: Discussionsupporting

confidence: 79%

Cell Damage Following Carbon Monoxide Releasing Molecule Exposure: Implications for Therapeutic Applications

Winburn

Gunatunga

McKernan

et al. 2012

Basic Clin Pharma Tox

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“…; Landgraf et al . ). Similarly, reduction of SERCA2a abundance decreases the propensity for Ca 2+ wave development and ventricular extrasystoles (Stokke et al .…”

Section: Discussionmentioning

confidence: 97%

Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII‐constitutive phosphorylation of RyR2 at site S2814

Mazzocchi

Sommese

Palomeque

et al. 2016

The Journal of Physiology

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Key pointsr Mice with Ca 2+ -calmodulin-dependent protein kinase (CaMKII) constitutive pseudo-phosphorylation of the ryanodine receptor RyR2 at Ser2814 (S2814D +/+ mice) exhibit a higher open probability of RyR2, higher sarcoplasmic reticulum (SR) Ca 2+ leak in diastole and increased propensity to arrhythmias under stress conditions. r We generated phospholamban (PLN)-deficient S2814D r A mathematical human myocyte model replicates these results and predicts the increase in SR Ca 2+ uptake required to prevent the arrhythmias induced by a CaMKII-dependent leaky RyR2.Abstract Mice with constitutive pseudo-phosphorylation at Ser2814-RyR2 (S2814D +/+ ) have increased propensity to arrhythmias under β-adrenergic stress conditions. Although abnormal Ca 2+ release from the sarcoplasmic reticulum (SR) has been linked to arrhythmogenesis, the role played by SR Ca 2+ uptake remains controversial. We tested the hypothesis that an increase in SR Ca 2+ uptake is able to rescue the increased arrhythmia propensity of S2814D +/+ mice. We generated phospholamban (PLN)-deficient/S2814D +/+ knock-in mice by crossing two colonies, S2814D

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“…For example, mitochondrial Ca 2+ retention may be crucially involved within the redistribution of [Ca 2+ ] cyt , to avoid harmful effects while accumulating in very high concentrations in the close proximity of mitochondria and Ca 2+ channels of the cell membrane or EPR/SR [ 109 – 111 ]. In addition, mitochondrial Ca 2+ cycling may be vital for governing the cytosolic Ca 2+ -waves [ 86 , 112 , 113 ]. To address the latter function of mitochondria within the the intracellular Ca 2+ homeostasis, we assessed the spontaneous Ca 2+ waves by confocal scanning fluorescence microscopy, using fluo-3 as a Ca 2+ sensor in a cell free system (an agarose gel supplemented with isolated SR vesicles, cardiac mitochondria, CK-based ATP regenerating system, and 5 mM ATP) [ 86 ].…”

Section: The Cellular Energetic Depression and Mitochondrial Cell Deamentioning

confidence: 99%

Mitochondria and Energetic Depression in Cell Pathophysiology

Seppet

Gruno

Peetsalu

et al. 2009

IJMS

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Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting OPEN ACCESSInt. J. Mol. Sci. 2009, 10 2253 from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell's ability to do work and control the intracellular Ca 2+ homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis.

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Inhibitors of SERCA and mitochondrial Ca-uniporter decrease velocity of calcium waves in rat cardiomyocytes

Cited by 18 publications

References 40 publications

Cell Damage Following Carbon Monoxide Releasing Molecule Exposure: Implications for Therapeutic Applications

Cell Damage Following Carbon Monoxide Releasing Molecule Exposure: Implications for Therapeutic Applications

Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII‐constitutive phosphorylation of RyR2 at site S2814

Mitochondria and Energetic Depression in Cell Pathophysiology

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