H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart

Christophe Depre; Li Wang; Xiangzhen Sui; Hongyu Qiu; Chull Hong; Nadia Hedhli; Audrey Ginion; Amy Shah; Michel Pelat; Luc Bertrand; Thomas Wagner; Vinciane Gaussin; Stephen F. Vatner

doi:10.1161/01.RES.0000201284.45482.e8

H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart

Christophe Depre, Li Wang, Xiangzhen Sui, Hongyu Qiu, Chull Hong, Nadia Hedhli, Audrey Ginion, Amy Shah, Michel Pelat, Luc Bertrand, Thomas Wagner, Vinciane Gaussin, Stephen F. Vatner

Rutgers, The State University

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

76 Scopus citations

Abstract

Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82±5% reduction in infarct size compared with wild-type (WT), which was similar to the 84±4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5′AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3β, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cε, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1α, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.

Original language	American English
Pages (from-to)	280-288
Number of pages	9
Journal	Circulation research
Volume	98
Issue number	2
DOIs	https://doi.org/10.1161/01.RES.0000201284.45482.e8
State	Published - Feb 2006

ASJC Scopus subject areas

Physiology
Cardiology and Cardiovascular Medicine

Keywords

AMPK
Akt
Apoptosis
Cell survival
Ischemia

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10.1161/01.RES.0000201284.45482.e8

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title = "H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart",

abstract = "Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82±5% reduction in infarct size compared with wild-type (WT), which was similar to the 84±4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5′AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3β, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cε, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1α, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.",

keywords = "AMPK, Akt, Apoptosis, Cell survival, Ischemia",

author = "Christophe Depre and Li Wang and Xiangzhen Sui and Hongyu Qiu and Chull Hong and Nadia Hedhli and Audrey Ginion and Amy Shah and Michel Pelat and Luc Bertrand and Thomas Wagner and Vinciane Gaussin and Vatner, {Stephen F.}",

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AU - Depre, Christophe

AU - Wang, Li

AU - Sui, Xiangzhen

AU - Qiu, Hongyu

AU - Hong, Chull

AU - Hedhli, Nadia

AU - Ginion, Audrey

AU - Shah, Amy

AU - Pelat, Michel

AU - Bertrand, Luc

AU - Wagner, Thomas

AU - Gaussin, Vinciane

AU - Vatner, Stephen F.

PY - 2006/2

Y1 - 2006/2

N2 - Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82±5% reduction in infarct size compared with wild-type (WT), which was similar to the 84±4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5′AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3β, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cε, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1α, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.

AB - Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82±5% reduction in infarct size compared with wild-type (WT), which was similar to the 84±4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5′AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3β, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cε, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1α, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.

KW - AMPK

KW - Akt

KW - Apoptosis

KW - Cell survival

KW - Ischemia

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C2 - 16373598

SN - 0009-7330

VL - 98

SP - 280

EP - 288

JO - Circulation research

JF - Circulation research

IS - 2

ER -

H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart

Abstract

ASJC Scopus subject areas

Keywords

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