The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury

Barbara A. Miller, Ju Fang Wang, Iwona Hirschler-Laszkiewicz, Erhe Gao, Jianliang Song, Xue Qian Zhang, Walter J. Koch, Muniswamy Madesh, Karthik Mallilankaraman, Tongda Gu, Shu Jen Chen, Kerry Keefer, Kathleen Conrad, Arthur M. Feldman, Joseph Y. Cheung

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 channels were functional since activation with H2O2 resulted in Ca2+ influx that was dependent on extracellular Ca2+, was significantly higher in wild-type (WT) myocytes compared with TRPM2 knockout (KO) myocytes, and inhibited by clotrimazole in WT myocytes. At rest, there were no differences in LV mass, heart rate, fractional shortening, and +dP/dt between WT and KO hearts. At 2-3 days after ischemia-reperfusion (I/R), despite similar areas at risk and infarct sizes, KO hearts had lower fractional shortening and +dP/dt compared with WT hearts. Compared with WT I/R myocytes, expression of the Na+/Ca2+ exchanger (NCX1) and NCX1 current were increased, expression of the α1-subunit of Na+-K+-ATPase and Na+ pump current were decreased, and action potential duration was prolonged in KO I/R myocytes. Post-I/R, intracellular Ca2+ concentration transients and contraction amplitudes were equally depressed in WT and KO myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation, levels of ROS were significantly higher in KO compared with WT LV myocytes. Compared with WT I/R hearts, oxygen radical scavenging enzymes (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factor) were lower, whereas NADPH oxidase was higher, in KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/Rinduced oxidative stress.

Original languageEnglish (US)
Pages (from-to)H1010-H1022
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number7
DOIs
StatePublished - Jun 10 2013

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Transient Receptor Potential Channels
Reperfusion Injury
Muscle Cells
Reperfusion
Ischemia
Clotrimazole
Forkhead Transcription Factors
Sarcolemma
NADPH Oxidase
Action Potentials
Reactive Oxygen Species
Oxidative Stress
Heart Rate

All Science Journal Classification (ASJC) codes

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

Cite this

Miller, Barbara A. ; Wang, Ju Fang ; Hirschler-Laszkiewicz, Iwona ; Gao, Erhe ; Song, Jianliang ; Zhang, Xue Qian ; Koch, Walter J. ; Madesh, Muniswamy ; Mallilankaraman, Karthik ; Gu, Tongda ; Chen, Shu Jen ; Keefer, Kerry ; Conrad, Kathleen ; Feldman, Arthur M. ; Cheung, Joseph Y. / The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury. In: American Journal of Physiology - Heart and Circulatory Physiology. 2013 ; Vol. 304, No. 7. pp. H1010-H1022.
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abstract = "The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 channels were functional since activation with H2O2 resulted in Ca2+ influx that was dependent on extracellular Ca2+, was significantly higher in wild-type (WT) myocytes compared with TRPM2 knockout (KO) myocytes, and inhibited by clotrimazole in WT myocytes. At rest, there were no differences in LV mass, heart rate, fractional shortening, and +dP/dt between WT and KO hearts. At 2-3 days after ischemia-reperfusion (I/R), despite similar areas at risk and infarct sizes, KO hearts had lower fractional shortening and +dP/dt compared with WT hearts. Compared with WT I/R myocytes, expression of the Na+/Ca2+ exchanger (NCX1) and NCX1 current were increased, expression of the α1-subunit of Na+-K+-ATPase and Na+ pump current were decreased, and action potential duration was prolonged in KO I/R myocytes. Post-I/R, intracellular Ca2+ concentration transients and contraction amplitudes were equally depressed in WT and KO myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation, levels of ROS were significantly higher in KO compared with WT LV myocytes. Compared with WT I/R hearts, oxygen radical scavenging enzymes (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factor) were lower, whereas NADPH oxidase was higher, in KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/Rinduced oxidative stress.",
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The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury. / Miller, Barbara A.; Wang, Ju Fang; Hirschler-Laszkiewicz, Iwona; Gao, Erhe; Song, Jianliang; Zhang, Xue Qian; Koch, Walter J.; Madesh, Muniswamy; Mallilankaraman, Karthik; Gu, Tongda; Chen, Shu Jen; Keefer, Kerry; Conrad, Kathleen; Feldman, Arthur M.; Cheung, Joseph Y.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 304, No. 7, 10.06.2013, p. H1010-H1022.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury

AU - Miller, Barbara A.

AU - Wang, Ju Fang

AU - Hirschler-Laszkiewicz, Iwona

AU - Gao, Erhe

AU - Song, Jianliang

AU - Zhang, Xue Qian

AU - Koch, Walter J.

AU - Madesh, Muniswamy

AU - Mallilankaraman, Karthik

AU - Gu, Tongda

AU - Chen, Shu Jen

AU - Keefer, Kerry

AU - Conrad, Kathleen

AU - Feldman, Arthur M.

AU - Cheung, Joseph Y.

PY - 2013/6/10

Y1 - 2013/6/10

N2 - The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 channels were functional since activation with H2O2 resulted in Ca2+ influx that was dependent on extracellular Ca2+, was significantly higher in wild-type (WT) myocytes compared with TRPM2 knockout (KO) myocytes, and inhibited by clotrimazole in WT myocytes. At rest, there were no differences in LV mass, heart rate, fractional shortening, and +dP/dt between WT and KO hearts. At 2-3 days after ischemia-reperfusion (I/R), despite similar areas at risk and infarct sizes, KO hearts had lower fractional shortening and +dP/dt compared with WT hearts. Compared with WT I/R myocytes, expression of the Na+/Ca2+ exchanger (NCX1) and NCX1 current were increased, expression of the α1-subunit of Na+-K+-ATPase and Na+ pump current were decreased, and action potential duration was prolonged in KO I/R myocytes. Post-I/R, intracellular Ca2+ concentration transients and contraction amplitudes were equally depressed in WT and KO myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation, levels of ROS were significantly higher in KO compared with WT LV myocytes. Compared with WT I/R hearts, oxygen radical scavenging enzymes (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factor) were lower, whereas NADPH oxidase was higher, in KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/Rinduced oxidative stress.

AB - The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 channels were functional since activation with H2O2 resulted in Ca2+ influx that was dependent on extracellular Ca2+, was significantly higher in wild-type (WT) myocytes compared with TRPM2 knockout (KO) myocytes, and inhibited by clotrimazole in WT myocytes. At rest, there were no differences in LV mass, heart rate, fractional shortening, and +dP/dt between WT and KO hearts. At 2-3 days after ischemia-reperfusion (I/R), despite similar areas at risk and infarct sizes, KO hearts had lower fractional shortening and +dP/dt compared with WT hearts. Compared with WT I/R myocytes, expression of the Na+/Ca2+ exchanger (NCX1) and NCX1 current were increased, expression of the α1-subunit of Na+-K+-ATPase and Na+ pump current were decreased, and action potential duration was prolonged in KO I/R myocytes. Post-I/R, intracellular Ca2+ concentration transients and contraction amplitudes were equally depressed in WT and KO myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation, levels of ROS were significantly higher in KO compared with WT LV myocytes. Compared with WT I/R hearts, oxygen radical scavenging enzymes (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factor) were lower, whereas NADPH oxidase was higher, in KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/Rinduced oxidative stress.

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