Temperature preconditioning of isolated rat hearts – a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore

Khaliulin, Igor; Clarke, Samantha J.; Lin, Hua; Parker, Joanna E.; Suleiman, M‐Saadeh; Halestrap, Andrew P.

doi:10.1113/jphysiol.2007.130369

Cited by 81 publications

(109 citation statements)

References 72 publications

(95 reference statements)

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…We and others have provided evidence showing that the cAMP signal transduction pathways are involved in mediating a number of cardioprotective effects (Lochner et al, 1999; Khaliulin et al, 2010; Khaliulin et al, 2014). Our work has also identified PKC as a critical component of cAMP/PKA‐induced cardioprotection (Khaliulin et al, 2007; Khaliulin et al, 2010). A major problem associated with targeting the cAMP/PKA pathway is the fact that this treatment has relied on stimulation of β‐adrenoceptors, which may be impaired in chronic heart failure due to hyperstimulation of β‐adrenoceptors, mediated via the sympathetic nervous system (Cannavo et al, 2013; Lymperopoulos et al, 2013).…”

Section: Introductionmentioning

confidence: 59%

“…Previously, we have shown on a similar model of I/R that H‐89 or chelerythrine alone at the concentration of 10 μM had no effect on I/R injury (Khaliulin et al, 2007; Khaliulin et al, 2010). For this reason, the groups of hearts with H‐89 or chelerythrine alone were not included in this study.…”

Section: Methodsmentioning

confidence: 80%

“…Earlier data show that PKA activation induced by stimulation of β‐adrenoceptors, triggers an ischaemic preconditioning (IP)‐like effect (Lochner et al, 1999) and that repeated stimulation with noradrenaline or isoprenaline mimics IP (Asimakis et al, 1994). Previously, we found that temperature preconditioning induced by a few short‐term episodes of hypothermic and normothermic perfusion (Khaliulin et al, 2007) is also mediated by PKA activation (Khaliulin et al, 2010). …”

Section: Discussionmentioning

confidence: 98%

See 2 more Smart Citations

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Khaliulin

Bond

James

et al. 2017

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and PurposeMyocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R.Experimental ApproachHearts from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocyte isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion. Functional recovery and myocardial injury during reperfusion (LDH release and infarct size) were evaluated. Activation of PKA and/or Epac in perfused hearts was induced using cell permeable cAMP analogues in the presence or absence of inhibitors of PKA, Epac and PKC. H9C2 cells and cardiomyocytes were used to assess activation of Epac and effect on Ca2+ transients.Key ResultsSelective activation of either PKA or Epac was found to trigger a positive inotropic effect, which was considerably enhanced when both pathways were simultaneously activated. Only combined activation of PKA and Epac induced marked cardioprotection against I/R injury. This was accompanied by PKCε activation and repressed by inhibitors of PKA, Epac or PKC.Conclusion and ImplicationsSimultaneous activation of both PKA and Epac induces an additive inotropic effect and confers optimal and marked cardioprotection against I/R injury. The latter effect is mediated by PKCε activation. This work has introduced a new therapeutic approach and targets to protect the heart against cardiac insults.

show abstract

Section: Introductionmentioning

confidence: 59%

Section: Methodsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Khaliulin

Bond

James

et al. 2017

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The beneficial effect of hypothermic preconditioning in cardiac tissue is ameliorated in part by administration of Compound C (Khaliulin et al 2007). The temperature-controlled group was maintained at 37°C-37.5°C during and after stroke.…”

Section: Resultsmentioning

confidence: 99%

Age-related changes in AMP-activated protein kinase after stroke

Liu

Benashski

Persky

et al. 2011

AGE

View full text Add to dashboard Cite

Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionary conserved energy sensor sensitive to changes in cellular AMP/ ATP ratio which is activated by phosphorylation (pAMPK). pAMPK levels decrease in peripheral tissues with age, but whether this also occurs in the aged brain, and how this contributes to the ability of the aged brain to cope with ischemic stress is unknown. This study investigated the activation of AMPK and the response to AMPK inhibition after induced stroke in both young and aged male mice. Baseline levels of phosphorylated AMPK were higher in aged brains compared to young mice. Strokeinduced a robust activation of AMPK in young mice, yet this response was muted in the aged brain. Young mice had larger infarct volumes compared with aged animals; however, more severe behavioral deficits and higher mortality were seen in aged mice after stroke. Inhibition of AMPK with Compound C decreased infarct size in young animals, but had no effect in aged mice. Compound C administration led to a reduction in brain ATP levels and induced hypothermia, which led to enhanced neuroprotection in young but not aged mice. This work demonstrates that aging increases baseline brain pAMPK levels; aged mice have a muted stroke-induced pAMPK response; and that AMPK inhibition and hypothermia are less efficacious neuroprotective agents in the aged brain. This has important translational relevance for the development of neuroprotective agents in preclinical models and our understanding of the enhanced metabolic stress experienced by the aged brain.

show abstract

“…Signaling pathways have substantial cross-talk, and pharmacologic inhibitor studies suggest a possible association between activation of PKCe and the energy-stress kinase AMPactivated protein kinase (AMPK) (10). AMPK is activated by changes in cellular energetics, but its activity is also modulated by other factors, including adiponectin, leptin, and macrophage migration inhibitory factor (11).…”

mentioning

confidence: 99%

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Qi²,

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Urocortin 2 (Ucn2), a peptide of the corticotropin-releasing factor (CRF) family, binds with high affinity to type 2 CRF receptors (CRFR2) on cardiomyocytes and confers protection against ischemia/reperfusion. The mechanisms by which the Ucn2-CRFR2 axis mitigates against ischemia/reperfusion injury remain incompletely delineated. Activation of AMP-activated protein kinase (AMPK) also limits cardiac damage during ischemia/reperfusion. AMPK is classically activated by alterations in cellular energetics; however, hormones, cytokines, and additional autocrine/paracrine factors also modulate its activity. We examined the effects of both the endogenous cardiac Ucn2 autocrine/paracrine pathway and Ucn2 treatment on AMPK regulation. Ucn2 treatment increased AMPK activation and downstream acetyl-CoA carboxylase phosphorylation and glucose uptake in isolated heart muscles. These actions were blocked by the CRFR2 antagonist anti-sauvagine-30 and by a PKCe translocation-inhibitor peptide (eV1-2). Hypoxia-induced AMPK activation was also blunted in heart muscles by preincubation with either anti-sauvagine-30, a neutralizing anti-Ucn2 antibody, or eV1-2. Treatment with Ucn2 in vivo augmented ischemic AMPK activation and reduced myocardial injury and cardiac contractile dysfunction after regional ischemia/reperfusion in mice. Ucn2 also directly activated AMPK in ex vivo-perfused mouse hearts and diminished injury and contractile dysfunction during ischemia/reperfusion. Thus, both Ucn2 treatment and the endogenous cardiac Ucn2 autocrine/paracrine pathway activate AMPK signaling pathway, via a PKCe-dependent mechanism, defining a Ucn2-CRFR2-PKCe-AMPK pathway that mitigates against ischemia/reperfusion injury. metabolism | cardiac function

show abstract

Temperature preconditioning of isolated rat hearts – a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore

Cited by 81 publications

References 72 publications

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Age-related changes in AMP-activated protein kinase after stroke

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Contact Info

Product

Resources

About