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

Nicholas E. Hoffman, Barbara A. Miller, Ju Fang Wang, John W. Elrod, Sudasan Rajan, Erhe Gao, Jianliang Song, Xue Qian Zhang, Iwona Hirschler-Laszkiewicz, Santhanam Shanmughapriya, Walter J. Koch, Arthur M. Feldman, Muniswamy Madesh, Joseph Y. Cheung

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)H637-H650
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number6
DOIs
StatePublished - Mar 15 2015

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Cardiac Myocytes
Energy Metabolism
Maintenance
Green Fluorescent Proteins
Muscle Cells
Oxygen Consumption
Doxorubicin
Reactive Oxygen Species
Reperfusion Injury
Cardiomyopathies
Oxidants
Adenoviridae
Superoxides
Reperfusion
Heart Ventricles
Oxidative Stress
Pressure
Injections
Wounds and Injuries
Hypoxia

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Hoffman, Nicholas E. ; Miller, Barbara A. ; Wang, Ju Fang ; 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. / Ca2+ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance. In: American Journal of Physiology - Heart and Circulatory Physiology. 2015 ; Vol. 308, No. 6. pp. H637-H650.
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Ca2+ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance. / Hoffman, Nicholas E.; Miller, Barbara A.; Wang, Ju Fang; 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.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 308, No. 6, 15.03.2015, p. H637-H650.

Research output: Contribution to journalArticle

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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.

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.

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