HSP70.1 and -70.3 are required for late-phase protection induced by  ischemic preconditioning of mouse hearts

Hampton, Craig R.; Shimamoto, Akira; Rothnie, Christine L.; Griscavage-Ennis, Jeaneatte; Chong, Albert J.; Dix, David J.; Verrier, Edward D.; Pohlman, Timothy H.

doi:10.1152/ajpheart.00596.2002

Cited by 62 publications

(58 citation statements)

References 46 publications

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“…Our study demonstrated that the protection conferred by Hsp70 occurs during the early phase of protection and is evident within 1 to 2 hours after I/R-mediated injury. A role for Hsp70 protecting the late phase of I/R injury has been demonstrated by Nakano et al 30 and Hampton et al 13 In the same model used in the present work, it was demonstrated that targeted deletion of the Hspa1a/1b genes abolished the late infarct-sparing effect of ischemic preconditioning after I/R injury. 13 It has been suggested that cardiac resistance against I/R insults after heat conditioning is a multifactorial phenomenon and includes more than one member of heat shock protein induction.…”

Section: Discussionsupporting

confidence: 78%

“…Levels of phospho-active kinases relative to total kinases showed a similar trend (C) *PϽ0.01, KO group (nϭ4, closed bar) vs WT group (nϭ4, open bar). Our study and the study of Hampton et al, 13 which use a genetic ablation of both Hsp70 genes, provide more direct evidence for a role of Hsp70 in its protection of the heart against I/R-related injury.…”

Section: Discussionsupporting

confidence: 64%

“…11,12 Recently, a knockout mouse strain has been developed that lacks func-tional Hspa1a and Hspa1b genes. 13,14 The Hspa1a gene and the Hspa1b gene encode the Hsp70 proteins, which only differ by one amino acid. Both are expressed in a wide range of tissues, constitutively as well as in response to a wide range of environmental stress.…”

Section: Clinical Perspective P 2597mentioning

confidence: 99%

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Deletion of the Inducible 70-kDa Heat Shock Protein Genes in Mice Impairs Cardiac Contractile Function and Calcium Handling Associated With Hypertrophy

et al. 2006

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Background-Hspa1a and Hspa1b genes encode stress-inducible 70-kDa heat shock proteins (Hsp70) that protect cells from insults such as ischemia. Mice with null mutations of both genes (KO) were generated, and their cardiac phenotype was explored. Methods and Results-Heart rate and blood pressures were normal in the KO mice. Hearts from KO mice were more susceptible to both functional and cellular damage by ischemia/reperfusion. Cardiac hypertrophy developed in Hsp70-KO mice. Ca 2ϩ transients in cardiomyocytes of KO mice showed a delayed (120%) calcium decline and decreased sarcoplasmic reticulum calcium content. Cell shortening was decreased by 35%, and rates of contraction and relaxation were slower by 40%. These alterations can be attributed to the absence of Hsp70 because viral expression of Hsp70 in KO cultured cardiomyocytes restored these parameters. One mechanism underlying myocyte dysfunction could be decreased SERCA2a expression. This hypothesis was supported by a prolonged calcium decline and decreased SERCA2a protein. Viral SERCA2a expression restored contractility and Ca 2ϩ transients. We examined the involvement of Jun N-terminal kinase (JNK), p38-mitogen-activated protein kinase (p38-MAPK), Raf-1, and extracellular signal-regulated kinase (ERK) in SERCA2a downregulation and the cardiac phenotype of KO mice. Levels of phosphorylated JNK, p38-MAPK, Raf-1, and ERK were elevated in KO hearts. Activation of the Raf-1-ERK pathway in normal cardiomyocytes resulted in decreased SERCA2a.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 64%

Section: Clinical Perspective P 2597mentioning

confidence: 99%

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Deletion of the Inducible 70-kDa Heat Shock Protein Genes in Mice Impairs Cardiac Contractile Function and Calcium Handling Associated With Hypertrophy

et al. 2006

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“…(1) The acquisition of ischemic tolerance depends on de novo protein synthesis, and induction of a host of neuroprotective stress proteins (Kato et al, 1994;Dewar et al, 1994;Noga et al, 1997;Poe and O'Neill, 1997;Akagawa et al, 1998;Shamloo et al, 1999;Ide et al, 1999;Samali et al, 1999;DeGracia et al, 2002;Budagova et al, 2003;Burda et al, 2003). Stress proteins such as molecular chaperones, folding enzymes and components of ubiquitin-proteasomal system reduce toxic aggregation of unfolded proteins (Nowak, 1991;Chen and Simon, 1997;Sharp et al, 1999;Hu et al, 2000Hu et al, , 2001Yenari et al, 1998Yenari et al, , 2002Kirino, 2002;Giffard et al, 2004;Hampton et al, 2003). (2) The recovery interval between sublethal ischemic preconditioning and the subsequent lethal period of ischemia is absolutely necessary for the acquisition of ischemic tolerance (Shamloo et al, 1999;Abe and Nowak, 2000;Burda et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Ischemic preconditioning prevents protein aggregation after transient cerebral ischemia

et al. 2005

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Transient cerebral ischemia leads to protein aggregation mainly in neurons destined to undergo delayed neuronal death after ischemia. This study utilized a rat transient cerebral ischemia model to investigate whether ischemic preconditioning is able to alleviate neuronal protein aggregation, thereby protecting neurons from ischemic neuronal damage. Ischemic preconditioning was introduced by a sublethal 3 min period of ischemia followed by 48 h of recovery. Brains from rats with either ischemic preconditioning or sham-surgery were then subjected to a subsequent 7 min period of ischemia followed by 30 min, 4, 24, 48 and 72 h of reperfusion. Protein aggregation and neuronal death were studied by electron and confocal microscopy, as well as by biochemical analyses. Seven minutes of cerebral ischemia alone induced severe protein aggregation after 4 h of reperfusion mainly in CA1 neurons destined to undergo delayed neuronal death (which took place after 72 h of reperfusion). Ischemic preconditioning reduced significantly protein aggregation and virtually eliminated neuronal death in CA1 neurons. Biochemical analyses revealed that ischemic preconditioning decreased accumulation of ubiquitin-conjugated proteins (ubi-proteins) and reduced free ubiquitin depletion after brain ischemia. Furthermore, ischemic preconditioning also reduced redistribution of heat shock cognate protein 70 and Hdj1 from cytosolic fraction to protein aggregate-containing fraction after brain ischemia. These results suggest that ischemic preconditioning decreases protein aggregation after brain ischemia. Keywords brain ischemia; preconditioning; protein aggregation; proteotoxicity; electron microscopy A brief episode of cerebral ischemia followed by reperfusion leads to delayed neuronal death in CA1 neurons at 48-72 h of reperfusion, while leaving dentate gyrus (DG), CA3 and most cortical neurons largely intact (Ito et al., 1975;Kirino, 1982;Smith et al., 1984). During this delayed period, neurons destined to undergo delayed neuronal death look normal under light microscopy. Under electron microscopy (EM), however, these CA1 neurons contain large quantities of intracellular protein aggregates (Hu et al., 2000).Cellular proteins in non-native states, i.e. unfolded (newly synthesized), misfolded, denatured, or damaged, expose the sticky hydrophobic segments, and are highly toxic to cells (Taylor et al., 2002;Dobson, 2003). There are several cellular defense systems to process proteins in non-native states and to reduce their proteotoxicity (Dobson, 2003 Proteasomal degradation of ubiquitin-conjugated proteins (ubi-proteins) is also strictly ATPdependent. Brain ischemia depletes ATP and changes intracellular homeostasis, thereby disabling ATP-dependent molecular chaperones and ubiquitin-proteasomal degradation, resulting in toxic aggregation of non-native proteins during the postischemic phase (Hu et al., 2000(Hu et al., , 2001.A short period of ischemia (ischemic preconditioning) that does not lead to neuronal death (sublethal), is able to i...

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“…For many years, heat shock and heat stress proteins have been regarded as intracellular molecules that have a range of housekeeping and cytoprotective functions (Evans et al 2010). Several studies have reported that the induction of HSP70 in myocardia can attenuate a variety of cardiac injuries caused by ischemia/reperfusion, hypoxia/reoxygenation, and heart failure (Esch et al 2002;Hampton et al 2003;Kuboki et al 2007). This suggests that the induction of HSP70 might be correlated with the acquisition of tolerance to stress.…”

Section: Discussionmentioning

confidence: 99%

HSP70 inhibits stress-induced cardiomyocyte apoptosis by competitively binding to FAF1

Gao¹,

Liu²,

Huang³

et al. 2015

Cell Stress and Chaperones

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Stress-induced cardiomyocyte apoptosis plays an important role in the pathogenesis of a variety of cardiovascular diseases. Our early studies showed that HSP70 effectively inhibited apoptosis, but the underlying mechanism remained unclear. Fas-associated factor 1 (FAF1) is a member of the Fas death-inducing signaling complex (Fas-DISC) that acts upstream of caspase-8. We investigated the interactions among FAF1, HSP70, and FAS in stressed cardiomyocytes to elucidate the protective mechanism of HSP70. FAS and caspase-3/8 activity was higher in cardiomyocytes undergoing stress-induced apoptosis in restraint-stressed rats compared with cardiomyocytes in non-stressed rats, which indicated that the Fas signaling pathway was activated after restraint stress. Geranylgeranylacetone (GGA) induced an increase in HSP70 expression, which reduced stress-induced apoptosis. Additionally, overexpression of HSP70 via transfection with the pEGFP-rHSP70 plasmid attenuated norepinephrine (NE)-induced apoptosis. FAF1 expression increased during stressinduced apoptosis, and overexpression of FAF1 exacerbated NE-induced apoptosis. We also found that HSP70 interacted with FAF1. Overexpression of HSP70 inhibited the binding of FAF1 to FAS in H9C2 cells, which indicated that HSP70 suppressed NE-induced apoptosis by competitively binding to FAF1. An N-terminal deletion mutant of HSP70 (HSP70-△N) was unable to interact with FAF1. After HSP70-△N was transfected into H9C2 cells, the cells were unable to attenuate the NE-induced increases in caspase-8 and apoptosis. These results indicate that the 1-120 sequence of HSP70 binds to FAF1, which alters the interactions between FAS and FAF1 and inhibits the activation of the Fas signaling pathway and apoptosis.

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HSP70.1 and -70.3 are required for late-phase protection induced by ischemic preconditioning of mouse hearts

Abstract: man. HSP70.1 and -70.3 are required for late-phase protection induced by ischemic preconditioning of mouse hearts.

Cited by 62 publications

References 46 publications

Deletion of the Inducible 70-kDa Heat Shock Protein Genes in Mice Impairs Cardiac Contractile Function and Calcium Handling Associated With Hypertrophy

Deletion of the Inducible 70-kDa Heat Shock Protein Genes in Mice Impairs Cardiac Contractile Function and Calcium Handling Associated With Hypertrophy

Ischemic preconditioning prevents protein aggregation after transient cerebral ischemia

HSP70 inhibits stress-induced cardiomyocyte apoptosis by competitively binding to FAF1

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