TRPM2 channels protect against cardiac ischemia-reperfusion injury: role of mitochondria.

J Biol Chem 2014 Mar 3;289(11):7615-29. Epub 2014 Feb 3.

From the Center of Translational Medicine.

Cardiac TRPM2 channels were activated by intracellular adenosine diphosphate-ribose and blocked by flufenamic acid. In adult cardiac myocytes the ratio of GCa to GNa of TRPM2 channels was 0.56 ± 0.02. To explore the cellular mechanisms by which TRPM2 channels protect against cardiac ischemia/reperfusion (I/R) injury, we analyzed proteomes from WT and TRPM2 KO hearts subjected to I/R. The canonical pathways that exhibited the largest difference between WT-I/R and KO-I/R hearts were mitochondrial dysfunction and the tricarboxylic acid cycle. Complexes I, III, and IV were down-regulated, whereas complexes II and V were up-regulated in KO-I/R compared with WT-I/R hearts. Western blots confirmed reduced expression of the Complex I subunit and other mitochondria-associated proteins in KO-I/R hearts. Bioenergetic analyses revealed that KO myocytes had a lower mitochondrial membrane potential, mitochondrial Ca(2+) uptake, ATP levels, and O2 consumption but higher mitochondrial superoxide levels. Additionally, mitochondrial Ca(2+) uniporter (MCU) currents were lower in KO myocytes, indicating reduced mitochondrial Ca(2+) uptake was likely due to both lower ψm and MCU activity. Similar to isolated myocytes, O2 consumption and ATP levels were also reduced in KO hearts. Under a simulated I/R model, aberrant mitochondrial bioenergetics was exacerbated in KO myocytes. Reactive oxygen species levels were also significantly higher in KO-I/R compared with WT-I/R heart slices, consistent with mitochondrial dysfunction in KO-I/R hearts. We conclude that TRPM2 channels protect the heart from I/R injury by ameliorating mitochondrial dysfunction and reducing reactive oxygen species levels.

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M113.533851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953274PMC
March 2014
34 Reads
26 Citations
4.573 Impact Factor

Publication Analysis

Top Keywords

trpm2 channels
20
ko-i/r hearts
12
mitochondrial dysfunction
12
channels protect
12
mitochondrial ca2+
12
mitochondrial
9
species levels
8
reactive oxygen
8
ca2+ uptake
8
atp levels
8
oxygen species
8
i/r injury
8
ko-i/r compared
8
protect cardiac
8
compared wt-i/r
8
trpm2
6
hearts
6
myocytes
5
levels
5
ko-i/r
5

Similar Publications