Loading...
TRPM2 Channels Protect against Cardiac Ischemia-Reperfusion Injury
Miller, Barbara A. Hoffman, Nicholas E. Zhang, Xue-Qian Wang, JuFang Rajan, Sudarsan Gao, Erhe Mallilankaraman, Karthik
Miller, Barbara A.
Hoffman, Nicholas E.
Zhang, Xue-Qian
Wang, JuFang
Rajan, Sudarsan
Gao, Erhe
Mallilankaraman, Karthik
Citations
Altmetric:
Genre
Journal article
Date
2014-03-14
Advisor
Committee member
Department
Nephrology
Biochemistry
Biochemistry
Permanent link to this record
Collections
Research Projects
Organizational Units
Journal Issue
DOI
https://doi.org/10.1074/jbc.m113.533851
Abstract
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 Ca2+ uptake, ATP levels, and O2 consumption but higher mitochondrial superoxide levels. Additionally, mitochondrial Ca2+ uniporter (MCU) currents were lower in KO myocytes, indicating reduced mitochondrial Ca2+ 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.
Description
Citation
Citation to related work
Elsevier
Has part
Journal of Biological Chemistry, Vol. 289, Iss. 11
ADA compliance
For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu