Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury

Ming Cai; Zachary M. Huttinger; Heng He; Weizhi Zhang; Feng Li; Lauren A. Goodman; Debra G. Wheeler; Lawrence J. Druhan; Jay L. Zweier; Karen M. Dwyer; Guanglong He; Anthony J.F. d'Apice; Simon C. Robson; Peter J. Cowan; Richard J. Gumina

doi:10.1016/j.yjmcc.2011.09.003

Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury

Ming Cai, Zachary M. Huttinger, Heng He, Weizhi Zhang, Feng Li, Lauren A. Goodman, Debra G. Wheeler, Lawrence J. Druhan, Jay L. Zweier, Karen M. Dwyer, Guanglong He, Anthony J.F. d'Apice, Simon C. Robson, Peter J. Cowan, Richard J. Gumina

Cardiovascular Medicine

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

Modulation of purinergic signaling is critical to myocardial homeostasis. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) which converts the proinflammatory molecules ATP or ADP to AMP is a key regulator of purinergic modulation. However, the salutary effects of transgenic over expression of ENTPD-1 on myocardial response to ischemic injury have not been tested to date. Therefore we hypothesized that ENTPD-1 over expression affords myocardial protection from ischemia-reperfusion injury via specific cell signaling pathways. ENTPD-1 transgenic mice, which over express human ENTPDase-1, and wild-type (WT) littermates were subjected to either ex vivo or in vivo ischemia-reperfusion injury. Infarct size, inflammatory cell infiltrate and intracellular signaling molecule activation were evaluated. Infarct size was significantly reduced in ENTPD-1 versus WT hearts in both ex vivo and in vivo studies. Following ischemia-reperfusion injury, ENTPD-1 cardiac tissues demonstrated an increase in the phosphorylation of the cellular signaling molecule extracellular signal-regulated kinases 1/2 (ERK 1/2) and glycogen synthase kinase-3β (GSK-3β). Resistance to myocardial injury was abrogated by treatment with a non-selective adenosine receptor antagonist, 8-SPT or the more selective A _2B adenosine receptor antagonist, MRS 1754, but not the A ₁ selective antagonists, DPCPX. Additionally, treatment with the ERK 1/2 inhibitor PD98059 or the mitochondrial permeability transition pore opener, atractyloside, abrogated the cardiac protection provided by ENTPDase-1 expression. These results suggest that transgenic ENTPDase-1 expression preferentially conveys myocardial protection from ischemic injury via adenosine A _2B receptor engagement and associated phosphorylation of the cellular protective signaling molecules, Akt, ERK 1/2 and GSK-3β that prevents detrimental opening of the mitochondrial permeability transition pore.

Original language	English (US)
Pages (from-to)	927-935
Number of pages	9
Journal	Journal of Molecular and Cellular Cardiology
Volume	51
Issue number	6
DOIs	https://doi.org/10.1016/j.yjmcc.2011.09.003
State	Published - Dec 2011

Keywords

Adenosine receptor
CD39
ERK 1/2
Ectonucleoside triphosphate diphosphohydrolase 1
GSK-3β
Myocardial ischemia
Reperfusion

ASJC Scopus subject areas

Molecular Biology
Cardiology and Cardiovascular Medicine

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10.1016/j.yjmcc.2011.09.003

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Cai, M., Huttinger, Z. M., He, H., Zhang, W., Li, F., Goodman, L. A., Wheeler, D. G., Druhan, L. J., Zweier, J. L., Dwyer, K. M., He, G., d'Apice, A. J. F., Robson, S. C., Cowan, P. J., & Gumina, R. J. (2011). Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury. Journal of Molecular and Cellular Cardiology, 51(6), 927-935. https://doi.org/10.1016/j.yjmcc.2011.09.003

Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury. / Cai, Ming; Huttinger, Zachary M.; He, Heng; Zhang, Weizhi; Li, Feng; Goodman, Lauren A.; Wheeler, Debra G.; Druhan, Lawrence J.; Zweier, Jay L.; Dwyer, Karen M.; He, Guanglong; d'Apice, Anthony J.F.; Robson, Simon C.; Cowan, Peter J.; Gumina, Richard J.

In: Journal of Molecular and Cellular Cardiology, Vol. 51, No. 6, 12.2011, p. 927-935.

Research output: Contribution to journal › Article › peer-review

Cai, M, Huttinger, ZM, He, H, Zhang, W, Li, F, Goodman, LA, Wheeler, DG, Druhan, LJ, Zweier, JL, Dwyer, KM, He, G, d'Apice, AJF, Robson, SC, Cowan, PJ & Gumina, RJ 2011, 'Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury', Journal of Molecular and Cellular Cardiology, vol. 51, no. 6, pp. 927-935. https://doi.org/10.1016/j.yjmcc.2011.09.003

Cai, Ming ; Huttinger, Zachary M. ; He, Heng ; Zhang, Weizhi ; Li, Feng ; Goodman, Lauren A. ; Wheeler, Debra G. ; Druhan, Lawrence J. ; Zweier, Jay L. ; Dwyer, Karen M. ; He, Guanglong ; d'Apice, Anthony J.F. ; Robson, Simon C. ; Cowan, Peter J. ; Gumina, Richard J. / Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury. In: Journal of Molecular and Cellular Cardiology. 2011 ; Vol. 51, No. 6. pp. 927-935.

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title = "Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury",

abstract = "Modulation of purinergic signaling is critical to myocardial homeostasis. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) which converts the proinflammatory molecules ATP or ADP to AMP is a key regulator of purinergic modulation. However, the salutary effects of transgenic over expression of ENTPD-1 on myocardial response to ischemic injury have not been tested to date. Therefore we hypothesized that ENTPD-1 over expression affords myocardial protection from ischemia-reperfusion injury via specific cell signaling pathways. ENTPD-1 transgenic mice, which over express human ENTPDase-1, and wild-type (WT) littermates were subjected to either ex vivo or in vivo ischemia-reperfusion injury. Infarct size, inflammatory cell infiltrate and intracellular signaling molecule activation were evaluated. Infarct size was significantly reduced in ENTPD-1 versus WT hearts in both ex vivo and in vivo studies. Following ischemia-reperfusion injury, ENTPD-1 cardiac tissues demonstrated an increase in the phosphorylation of the cellular signaling molecule extracellular signal-regulated kinases 1/2 (ERK 1/2) and glycogen synthase kinase-3β (GSK-3β). Resistance to myocardial injury was abrogated by treatment with a non-selective adenosine receptor antagonist, 8-SPT or the more selective A 2B adenosine receptor antagonist, MRS 1754, but not the A 1 selective antagonists, DPCPX. Additionally, treatment with the ERK 1/2 inhibitor PD98059 or the mitochondrial permeability transition pore opener, atractyloside, abrogated the cardiac protection provided by ENTPDase-1 expression. These results suggest that transgenic ENTPDase-1 expression preferentially conveys myocardial protection from ischemic injury via adenosine A 2B receptor engagement and associated phosphorylation of the cellular protective signaling molecules, Akt, ERK 1/2 and GSK-3β that prevents detrimental opening of the mitochondrial permeability transition pore.",

keywords = "Adenosine receptor, CD39, ERK 1/2, Ectonucleoside triphosphate diphosphohydrolase 1, GSK-3β, Myocardial ischemia, Reperfusion",

author = "Ming Cai and Huttinger, {Zachary M.} and Heng He and Weizhi Zhang and Feng Li and Goodman, {Lauren A.} and Wheeler, {Debra G.} and Druhan, {Lawrence J.} and Zweier, {Jay L.} and Dwyer, {Karen M.} and Guanglong He and d'Apice, {Anthony J.F.} and Robson, {Simon C.} and Cowan, {Peter J.} and Gumina, {Richard J.}",

note = "Funding Information: This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute Grants K08-HL094703 and R21- HL096038, an American Heart Association-Great Rivers Affiliate Student Undergraduate Research Fellowship Grant 10UFEL4180090 (ZMH, HH and LAG), the Davis Heart and Lung Research Institute and Ross Academic Advisory Committee (RJG). ",

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doi = "10.1016/j.yjmcc.2011.09.003",

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pages = "927--935",

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T1 - Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury

AU - Cai, Ming

AU - Huttinger, Zachary M.

AU - He, Heng

AU - Zhang, Weizhi

AU - Li, Feng

AU - Goodman, Lauren A.

AU - Wheeler, Debra G.

AU - Druhan, Lawrence J.

AU - Zweier, Jay L.

AU - Dwyer, Karen M.

AU - He, Guanglong

AU - d'Apice, Anthony J.F.

AU - Robson, Simon C.

AU - Cowan, Peter J.

AU - Gumina, Richard J.

N1 - Funding Information: This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute Grants K08-HL094703 and R21- HL096038, an American Heart Association-Great Rivers Affiliate Student Undergraduate Research Fellowship Grant 10UFEL4180090 (ZMH, HH and LAG), the Davis Heart and Lung Research Institute and Ross Academic Advisory Committee (RJG).

PY - 2011/12

Y1 - 2011/12

N2 - Modulation of purinergic signaling is critical to myocardial homeostasis. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) which converts the proinflammatory molecules ATP or ADP to AMP is a key regulator of purinergic modulation. However, the salutary effects of transgenic over expression of ENTPD-1 on myocardial response to ischemic injury have not been tested to date. Therefore we hypothesized that ENTPD-1 over expression affords myocardial protection from ischemia-reperfusion injury via specific cell signaling pathways. ENTPD-1 transgenic mice, which over express human ENTPDase-1, and wild-type (WT) littermates were subjected to either ex vivo or in vivo ischemia-reperfusion injury. Infarct size, inflammatory cell infiltrate and intracellular signaling molecule activation were evaluated. Infarct size was significantly reduced in ENTPD-1 versus WT hearts in both ex vivo and in vivo studies. Following ischemia-reperfusion injury, ENTPD-1 cardiac tissues demonstrated an increase in the phosphorylation of the cellular signaling molecule extracellular signal-regulated kinases 1/2 (ERK 1/2) and glycogen synthase kinase-3β (GSK-3β). Resistance to myocardial injury was abrogated by treatment with a non-selective adenosine receptor antagonist, 8-SPT or the more selective A 2B adenosine receptor antagonist, MRS 1754, but not the A 1 selective antagonists, DPCPX. Additionally, treatment with the ERK 1/2 inhibitor PD98059 or the mitochondrial permeability transition pore opener, atractyloside, abrogated the cardiac protection provided by ENTPDase-1 expression. These results suggest that transgenic ENTPDase-1 expression preferentially conveys myocardial protection from ischemic injury via adenosine A 2B receptor engagement and associated phosphorylation of the cellular protective signaling molecules, Akt, ERK 1/2 and GSK-3β that prevents detrimental opening of the mitochondrial permeability transition pore.

AB - Modulation of purinergic signaling is critical to myocardial homeostasis. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) which converts the proinflammatory molecules ATP or ADP to AMP is a key regulator of purinergic modulation. However, the salutary effects of transgenic over expression of ENTPD-1 on myocardial response to ischemic injury have not been tested to date. Therefore we hypothesized that ENTPD-1 over expression affords myocardial protection from ischemia-reperfusion injury via specific cell signaling pathways. ENTPD-1 transgenic mice, which over express human ENTPDase-1, and wild-type (WT) littermates were subjected to either ex vivo or in vivo ischemia-reperfusion injury. Infarct size, inflammatory cell infiltrate and intracellular signaling molecule activation were evaluated. Infarct size was significantly reduced in ENTPD-1 versus WT hearts in both ex vivo and in vivo studies. Following ischemia-reperfusion injury, ENTPD-1 cardiac tissues demonstrated an increase in the phosphorylation of the cellular signaling molecule extracellular signal-regulated kinases 1/2 (ERK 1/2) and glycogen synthase kinase-3β (GSK-3β). Resistance to myocardial injury was abrogated by treatment with a non-selective adenosine receptor antagonist, 8-SPT or the more selective A 2B adenosine receptor antagonist, MRS 1754, but not the A 1 selective antagonists, DPCPX. Additionally, treatment with the ERK 1/2 inhibitor PD98059 or the mitochondrial permeability transition pore opener, atractyloside, abrogated the cardiac protection provided by ENTPDase-1 expression. These results suggest that transgenic ENTPDase-1 expression preferentially conveys myocardial protection from ischemic injury via adenosine A 2B receptor engagement and associated phosphorylation of the cellular protective signaling molecules, Akt, ERK 1/2 and GSK-3β that prevents detrimental opening of the mitochondrial permeability transition pore.

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Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury

Abstract

Keywords

ASJC Scopus subject areas

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