TY - JOUR
T1 - Ca2+ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance
AU - Hoffman, Nicholas E.
AU - Miller, Barbara A.
AU - Wang, Ju Fang
AU - Elrod, John W.
AU - Rajan, Sudasan
AU - Gao, Erhe
AU - Song, Jianliang
AU - Zhang, Xue Qian
AU - Hirschler-Laszkiewicz, Iwona
AU - Shanmughapriya, Santhanam
AU - Koch, Walter J.
AU - Feldman, Arthur M.
AU - Madesh, Muniswamy
AU - Cheung, Joseph Y.
N1 - Publisher Copyright:
© 2015 the American Physiological Society.
PY - 2015/3/15
Y1 - 2015/3/15
N2 - Ubiquitously expressed Trpm2 channel limits oxidative stress and preserves mitochondrial function. We first demonstrated that intracellular Ca2+ concentration increase after Trpm2 activation was due to direct Ca2+ influx and not indirectly via reverse Na+/Ca2+ exchange. To elucidate whether Ca2+ 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 (O2.−) levels in gKO myocytes. After hypoxia-reoxygenation (H/R), Trpm2 but not E906D or P1018L (inactivates Trpm2 current) lowered O2.− levels in gKO myocytes and only in the presence of extracellular Ca2+, indicating sustained Ca2+ 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 Ca2+ influx is necessary to maintain mitochondrial function and protect against H/R injury; 2) Ca2+ 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.
AB - Ubiquitously expressed Trpm2 channel limits oxidative stress and preserves mitochondrial function. We first demonstrated that intracellular Ca2+ concentration increase after Trpm2 activation was due to direct Ca2+ influx and not indirectly via reverse Na+/Ca2+ exchange. To elucidate whether Ca2+ 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 (O2.−) levels in gKO myocytes. After hypoxia-reoxygenation (H/R), Trpm2 but not E906D or P1018L (inactivates Trpm2 current) lowered O2.− levels in gKO myocytes and only in the presence of extracellular Ca2+, indicating sustained Ca2+ 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 Ca2+ influx is necessary to maintain mitochondrial function and protect against H/R injury; 2) Ca2+ 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.
KW - Cardiac Trpm2 currents
KW - Doxorubicin cardiomyopathy
KW - Hypoxia-reoxygenation
KW - Ischemic cardiomyopathy
KW - Mitochondrial superoxide
KW - Voltage-independent Ca channels
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U2 - 10.1152/ajpheart.00720.2014
DO - 10.1152/ajpheart.00720.2014
M3 - Article
C2 - 25576627
AN - SCOPUS:84937510947
SN - 0363-6135
VL - 308
SP - H637-H650
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 6
ER -