Ca^sup 2+^ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance

Ubiquitously expressed Trpm2 channel limits oxidative stress and preserves mitochondrial function. We first demonstrated that intracellular Ca... concentration increase after Trpm2 activation was due to direct Ca... influx and not indirectly via reverse Na+/Ca... exchange. To elucidate whether Ca......

Full description

Saved in:
Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2015-03, Vol.308 (6), p.H637
Main Authors: Hoffman, Nicholas E, Miller, Barbara A, Wang, JuFang, Elrod, John W, Rajan, Sudasan, Gao, Erhe, Song, Jianliang, Zhang, Xue-Qian, Hirschler-Laszkiewicz, Iwona, Shanmughapriya, Santhanam, Koch, Walter J, Feldman, Arthur M, Madesh, Muniswamy, Cheung, Joseph Y
Format: Article
Language:English
Subjects:
Biochemistry
Blood pressure
Calcium
Cardiovascular system
Cells
Energy
Oxidative stress
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Ubiquitously expressed Trpm2 channel limits oxidative stress and preserves mitochondrial function. We first demonstrated that intracellular Ca... concentration increase after Trpm2 activation was due to direct Ca... influx and not indirectly via reverse Na+/Ca... exchange. To elucidate whether Ca... entry via Trpm2 is required to maintain cellular bioenergetics, we injected adenovirus expressing green fluorescent protein (GFP), wild-type (WT) Trpm2, and loss-of-function (E960D) Trpm2 mutant into left ventricles of global Trpm2 knockout (gKO) or WT hearts. 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...) levels in gKO myocytes. After hypoxia-reoxygenation (H/R), Trpm2 but not E906D or P1018L (inactivates Trpm2 current) lowered O... levels in gKO myocytes and only in the presence of extracellular Ca..., indicating sustained Ca... 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 (+dP/dt) than WT hearts in vivo. After doxorubicin treatment, Trpm2 KO mice had worse survival and lower +dP/dt. We conclude 1) cardiac Trpm2-mediated Ca... influx is necessary to maintain mitochondrial function and protect against H/R injury; 2) Ca... 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. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0363-6135
1522-1539