TRPM2 Channels Protect against Cardiac Ischemia-Reperfusion Injury

Miller, Barbara A.; Hoffman, Nicholas E.; Merali, Salim; Zhang, Xue Qian; Wang, Ju Fang; Rajan, Sudarsan; Shanmughapriya, Santhanam; Gao, Erhe; Barrero, Carlos; Mallilankaraman, Karthik; Song, Jianliang; Gu, Tongda; Hirschler-Laszkiewicz, Iwona; Koch, Walter J.; Feldman, Arthur M.; Madesh, Muniswamy; Cheung, Joseph Y.

doi:10.1074/jbc.m113.533851

Cited by 81 publications

(134 citation statements)

References 59 publications

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“…TRPM2 expressed in lysosomes controls intracellular calcium release in dendritic cells and pancreatic β cells (36,49). Thus, it is possible that TRPM2 affects injury in PTCs at intracellular loci, such as mitochondria or lysosomes, rather than through ion transport into the cell (50).…”

Section: Discussionmentioning

confidence: 99%

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

Gao¹,

Wang²,

Tadagavadi³

et al. 2014

J. Clin. Invest.

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103

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Measurement of TBARs. The measurement of TBARS in the kidney was based on the formation of malondialdehyde (MDA) as described by Liu et al. (87).Statistics. All assays were performed in duplicate or triplicate. Data are reported as the means ± SEM. Statistical significance was assessed by an unpaired, 2-tailed Student's t test for single comparison or by ANOVA for multiple comparisons. P < 0.05 was considered statistically significant. GraphPad Prism (GraphPad Software) was used for statistical analyses and graphs.Study approval. All experiments involving mice were approved by the

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Section: Discussionmentioning

confidence: 99%

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

Gao¹,

Wang²,

Tadagavadi³

et al. 2014

J. Clin. Invest.

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103

101

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“…After break-in, cells were subjected to voltage ramp (ϩ100 to Ϫ100 mV; 500 mV/s). In some experiments, ADPR (300 M) was included in pipette solutions to activate Trpm2 channels (22,26). In other experiments, after full activation of Trpm2 channels by ADPR, flufenamic acid (0.5 mM) was added to the extracellular medium to inhibit ITrpm2 (19,26).…”

Section: Methodsmentioning

confidence: 99%

“…Trpm2 currents (I Trpm2) were measured at 30°C in transfected HEK293 cells and Adv-infected LV myocytes (cultured for 24 h) with whole cell patch-clamp (26,27,39,44,47). Fire-polished pipettes (tip diameter 2 to 3 m for HEK293 cells and 4 -6 m for myocytes) were used.…”

Section: Methodsmentioning

confidence: 99%

“…After ischemia/reperfusion (I/R), global Trpm2 knockout (gKO) hearts exhibited reduced contractility when compared with wild-type (WT)-I/R hearts (27). Although results from single cell studies suggest that mitochondrial dysfunction is a result of Trpm2 deficiency in gKO myocytes (26), the use of the whole body knockout mouse reduces the ability to specifically define the role of the cardiac Trpm2 in protecting the heart from I/R injury. In addition, whether Ca 2ϩ influx through activated Trpm2 is required for ameliorating mitochondrial dysfunction was not addressed in previous studies.…”

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confidence: 99%

“…In adult cardiac myocytes, Trpm2 is activated by H 2 O 2 and intracellular adenosine diphosphate-ribose (ADPR), inhibited by clotrimazole and flufenamic acid, does not inactivate, and has a conductance for Ca 2ϩ that is ϳ50% of Na ϩ (26,27). After ischemia/reperfusion (I/R), global Trpm2 knockout (gKO) hearts exhibited reduced contractility when compared with wild-type (WT)-I/R hearts (27).…”

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confidence: 99%

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Ca²⁺entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance

Hoffman

Miller

Wang

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Five days post-injection, gKO-GFP heart slices had higher reactive oxygen species (ROS) levels but lower oxygen consumption rate (OCR) than WT-GFP heart slices. Trpm2 but not E960D decreased ROS and restored OCR in gKO hearts back to normal levels. In gKO myocytes expressing Trpm2 or its mutants, Trpm2 but not E960D reduced the elevated mitochondrial superoxide (O 2 .Ϫ ) levels in gKO myocytes. After hypoxia-reoxygenation (H/R), Trpm2 but not E906D or P1018L (inactivates Trpm2 current) lowered O 2 .Ϫ levels in gKO myocytes and only in the presence of extracellular Ca 2ϩ , indicating sustained Ca 2ϩ entry is necessary for Trpm2-mediated preservation of mitochondrial function. After ischemic-reperfusion (I/R), cardiac-specific Trpm2 KO hearts exhibited lower maximal first time derivative of LV pressure rise (ϩdP/dt) than WT hearts in vivo. After doxorubicin treatment, Trpm2 KO mice had worse survival and lower ϩdP/dt. We conclude 1) cardiac Trpm2-mediated Ca 2ϩ influx is necessary to maintain mitochondrial function and protect against H/R injury; 2) Ca 2ϩ influx via cardiac Trpm2 confers protection against H/R and I/R injury by reducing mitochondrial oxidants; and 3) Trpm2 confers protection in doxorubicin cardiomyopathy. ischemic cardiomyopathy; doxorubicin cardiomyopathy; voltage-independent Ca 2ϩ channels; cardiac Trpm2 currents; mitochondrial superoxide; hypoxia-reoxygenation IN MAMMALIAN CELLS, THE TRANSIENT receptor potential (Trp) protein superfamily is a diverse group of voltage-independent, cation-permeable channels organized into six subfamilies based on amino acid sequence homology (9, 30). Monomeric Trp proteins have six putative transmembrane (TM) domains and intracellular NH 2 and COOH termini. To form a functional channel, Trp proteins assemble into either homo-or heterotetramers, with the putative pore formed by loops between the fifth and sixth TM domains (21, 23). The Trp-melastatin (Trpm) subfamily consists of eight mammalian members (Trpm1-Trpm8)(30), of which Trpm2 (27), -m4, -m5, and -m6 (49) are expressed in the heart. Although Trpm4 is associated with conduction abnormalities and cardiac arrhythmias (1, 36), there is little information on the physiological and pathophysiological function of Trpm2 in the heart.

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Mitochondrial dysfunction in human immunodeficiency virus‐1 transgenic mouse cardiac myocytes

Cheung

Gordon

Wang

et al. 2018

Journal Cellular Physiology

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The pathophysiology of human immunodeficiency virus (HIV)-associated cardiomyopathy remains uncertain. We used HIV-1 transgenic (Tg26) mice to explore mechanisms by which HIV-related proteins impacted on myocyte function. Compared to adult ventricular myocytes isolated from nontransgenic (wild type [WT]) littermates, Tg26 myocytes had similar mitochondrial membrane potential (ΔΨ ) under normoxic conditions but lower Δ Ψ after hypoxia/reoxygenation (H/R). In addition, Δ Ψ in Tg26 myocytes failed to recover after Ca challenge. Functionally, mitochondrial Ca uptake was severely impaired in Tg26 myocytes. Basal and maximal oxygen consumption rates (OCR) were lower in normoxic Tg26 myocytes, and further reduced after H/R. Complex I subunit and ATP levels were lower in Tg26 hearts. Post-H/R, mitochondrial superoxide (O ) levels were higher in Tg26 compared to WT myocytes. Overexpression of B-cell lymphoma 2-associated athanogene 3 (BAG3) reduced O levels in hypoxic WT and Tg26 myocytes back to normal. Under normoxic conditions, single myocyte contraction dynamics were similar between WT and Tg26 myocytes. Post-H/R and in the presence of isoproterenol, myocyte contraction amplitudes were lower in Tg26 myocytes. BAG3 overexpression restored Tg26 myocyte contraction amplitudes to those measured in WT myocytes post-H/R. Coimmunoprecipitation experiments demonstrated physical association of BAG3 and the HIV protein Tat. We conclude: (a) Under basal conditions, mitochondrial Ca uptake, OCR, and ATP levels were lower in Tg26 myocytes; (b) post-H/R, Δ Ψ was lower, mitochondrial O levels were higher, and contraction amplitudes were reduced in Tg26 myocytes; and (c) BAG3 overexpression decreased O levels and restored contraction amplitudes to normal in Tg26 myocytes post-H/R in the presence of isoproterenol.

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TRPM2 Channels Protect against Cardiac Ischemia-Reperfusion Injury

Cited by 81 publications

References 59 publications

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

Ca²⁺entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance

Mitochondrial dysfunction in human immunodeficiency virus‐1 transgenic mouse cardiac myocytes

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TRPM2 Channels Protect against Cardiac Ischemia-Reperfusion Injury

Cited by 81 publications

References 59 publications

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

Ca2+entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance

Mitochondrial dysfunction in human immunodeficiency virus‐1 transgenic mouse cardiac myocytes

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Ca²⁺entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance