Preconditioning the Diabetic Heart

Tsang, Andrew; Hausenloy, Derek J.; Mocanu, Mihaela M.; Carr, Richard D.; Yellon, Derek M.

doi:10.2337/diabetes.54.8.2360

Cited by 226 publications

(240 citation statements)

References 38 publications

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“…Considerable evidence indicates that hypercholesterolemia abrogates both early [20] and late PC [21,22], although the effects on early PC remain controversial [23]. In addition, it appears that early and late PC are either attenuated or absent in the presence of diabetes [24][25][26]. No information is available regarding the impact of hypertension on PC.…”

Section: Cox-2 Involvement In Pcmentioning

confidence: 99%

The late phase of preconditioning and its natural clinical application—gene therapy

Bolli

Tang

et al. 2007

Heart Fail Rev

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There is little doubt that the discovery of ischemic preconditioning (PC) has been one of the fundamental milestones in the field of ischemic biology in the past 20 years. The purpose of this article is to review the pathophysiology and molecular basis of the late phase of myocardial PC. The exploitation of late PC for the development of novel gene therapy strategies aimed at inducing a permanently preconditioned cardiac phenotype (prophylactic cardioprotection) will also be discussed. Deciphering the mechanism of late PC has not only conceptual interest but also a considerable therapeutic implications, since transfer of the genes that underlie late PC would be expected to replicate the salubrious effects of this response of the heart to stress.

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Section: Cox-2 Involvement In Pcmentioning

confidence: 99%

The late phase of preconditioning and its natural clinical application—gene therapy

Bolli

Tang

et al. 2007

Heart Fail Rev

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“…Multiple signalling proteins/cascades are dysregulated in the diabetic heart, including extracellular signal-regulated kinase 1 (ERK1), signal transducer and activator of transcription 3 (STAT3) and AKT (a key downstream target of PI3K) [4,[16][17][18][19]. A critical step in developing better therapeutics is to understand which signalling events represent key mechanisms in the development of cardiomyopathy in a setting of hyperglycaemia.…”

Section: Introductionmentioning

confidence: 99%

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

et al. 2012

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Aims/hypothesis Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.Methods Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominantnegative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed. Results Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22 phox and apoptosis signalregulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22 phox expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function. Conclusions/interpretation These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.

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“…In our present study, both IPost and RVP-induced postconditioning nonsignificantly enhanced Akt phosphorylation without affecting ERK1/2 and STAT3 at the beginning of reperfusion. Although several studies showed increased phosphorylation of Akt and/or ERK due to IPost (Tsang et al, 2004;Yang et al, …”

Section: Figurementioning

confidence: 99%

Rapid ventricular pacing‐induced postconditioning attenuates reperfusion injury: effects on peroxynitrite, RISK and SAFE pathways

Pipicz

Varga

Kupai

et al. 2015

British J Pharmacology

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Background and PurposeRapid ventricular pacing (RVP) applied before an index ischaemia has anti‐ischaemic effects. Here, we investigated whether RVP applied after index ischaemia attenuates reperfusion injury and whether peroxynitrite, reperfusion injury salvage kinase (RISK) and survival activating factor enhancement (SAFE) pathways as well as haem oxygenase 1 (HO1) are involved in the mechanism of RVP‐induced postconditioning.Experimental ApproachLangendorff perfused rat hearts were subjected to 30 min regional ischaemia and 120 min reperfusion with or without ischaemic postconditioning (6 × 10/10 s reperfusion/ischaemia; IPost) or RVP (6 × 10/10 s non‐pacing/rapid pacing at 600 bpm) applied at the onset of reperfusion.Key ResultsMeta‐analysis of our previous studies revealed an association between longer reperfusion‐induced ventricular tachycardia/fibrillation with decreased infarct size. In the present experiments, we tested whether RVP is cardioprotective and found that both IPost and RVP significantly decreased infarct size; however, only RVP attenuated the incidence of reperfusion‐induced ventricular tachycardia. Both postconditioning methods increased the formation of cardiac 3‐nitrotyrosine and superoxide, and non‐significantly enhanced Akt phosphorylation at the beginning of reperfusion without affecting ERK1/2 and STAT3, while IPost alone induced HO1. Application of brief ischaemia/reperfusion cycles or RVP without preceding index ischaemia also facilitated peroxynitrite formation; nevertheless, only brief RVP increased STAT3 phosphorylation.Conclusions and ImplicationsShort periods of RVP at the onset of reperfusion are cardioprotective and increase peroxynitrite formation similarly to IPost and thus may serve as an alternative postconditioning method. However, downstream mechanisms of the protection elicited by IPost and RVP seem to be partially different.Linked ArticlesThis article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8

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Preconditioning the Diabetic Heart

Cited by 226 publications

References 38 publications

The late phase of preconditioning and its natural clinical application—gene therapy

The late phase of preconditioning and its natural clinical application—gene therapy

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

Rapid ventricular pacing‐induced postconditioning attenuates reperfusion injury: effects on peroxynitrite, RISK and SAFE pathways

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