PI3K(p110α) Protects Against Myocardial Infarction-Induced Heart Failure

Lin, Ruby C.Y.; Weeks, Kate L.; Gao, Xiao‐Ming; Williams, Rohan B.H.; Bernardo, Bianca C.; Kiriazis, Helen; Matthews, Vance B.; Woodcock, Elizabeth A.; Bouwman, Russell D.; Mollica, Janelle P.; Speirs, Helen J.L.; Dawes, Ian W.; Daly, Roger J.; Shioi, Tetsuo; Izumo, Seigo; Febbraio, Mark A.; Du, Xiao‐Jun; McMullen, Julie R.

doi:10.1161/atvbaha.109.201988

Cited by 152 publications

(143 citation statements)

References 45 publications

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“…In the current study, NADPHdriven superoxide generation was increased in diabetic Ntg hearts compared with non-diabetic Ntg hearts, and this was accompanied by increased production of a membraneassociated subunit of NADPH oxidase (p22 phox ). The p22 phox NADPH subunit was the focus of this study because it was the only subunit that was differentially regulated in the hearts of PI3K-Tg mice under control or sham conditions based on previous microarray data [12]. Interestingly, superoxide generation and p22 phox in the current study were higher in hearts from non-diabetic dnPI3K compared with non-diabetic Ntg mice, and remained elevated in a setting of diabetes.…”

Section: Discussionmentioning

confidence: 57%

“…Thus, new therapeutic strategies to protect the heart in the setting of diabetes are greatly needed. We have previously demonstrated that increased activation of phosphoinositide 3-kinase (PI3K)(p110α) in the heart is protective in pathological settings in which the heart is subjected to a localised cardiac insult such as aortic constriction (pressure overload) or coronary artery ligation (myocardial infarction) [12][13][14]. However, whether PI3K (p110α) can protect the heart against diabetic cardiomyopathy caused by global hyperglycaemia is unknown.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 57%

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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“…Grb14 is highly expressed in the mouse heart compared with other tissues. Three miRNAs were also highly correlated with Grb14, namely miR-210, miR-34a and miR-222 [91] .…”

Section: Therapeutic Opportunitiesmentioning

confidence: 93%

miRNome in myocardial infarction: Future directions and perspective

Boštjančič

Glavač

2014

WJC

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MicroRNAs (miRNAs), which are small and non-coding RNAs, are genome encoded from viruses to humans. They contribute to various developmental, physiological and pathological processes in living organisms. A huge amount of research results revealed that miRNAs regulate these processes also in the heart. miRNAs may have cell-type-specific or tissue-specific expression patterns or may be expressed ubiquitously. Primary studies of miRNA involvement in hypertrophy, heart failure and myocardial infarction analyzed miRNAs that are enriched in or specific for cardiomyocytes; however, growing evidence suggest that other miRNAs, not cardiac or muscle-specific, play a significant role in cardiovascular disease. Abnormal miRNA regulation has been shown to be involved in cardiac diseases, suggesting that miRNAs might affect cardiac structure and function. In this review, we focus on miRNAs that have been found to contribute to the pathogenesis of myocardial infarction (MI) and the response post-MI and characterized as diagnostic, prognostic and therapeutic targets. The majority of these studies were performed using mouse and rat models of MI, with a focus on the identification of basic cellular and molecular pathways involved in MI and in the response post-MI. Much research has also been performed on animal and human plasma samples from MI individuals to identify miRNAs that are possible prognostic and/or diagnostic targets of MI and other MI-related diseases. A large proportion of research is focused on miRNAs as promising therapeutic targets and biomarkers of drug responses and/or stem cell treatment approaches. However, only a few studies have described miRNA expression in human heart tissue following MI.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: MicroRNAs; Myocardial infarction; Human; Animal models; Biomarkers and targets Core tip: MicroRNAs (miRNAs) contribute to various developmental, physiological and pathological processes in the heart. Cardiac diseases show abnormal miRNA regulation. Primary studies of miRNA involvement in cardiac disease analyzed mainly miRNAs that enriched in or specific for cardiomyocytes; however, growing evidence suggests that other cell-type-specific or ubiquitously expressed miRNAs are also involved in cardiovascular disease. miRNAs were found to contribute to the pathogenesis of myocardial infarction (MI) and post-MI. The majority of studies focused on miRNAs in animal models of MI, in human and animal plasma samples of MI (prognostic and diagnostic targets), and on miRNAs as promising therapeutic targets.Boštjančič E, Glavač D. miRNome in myocardial infarction: Future directions and perspective. World J Cardiol 2014; 6(9): 939-958 Available from:

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“…However, longer term outcomes from myocardial infarction (Lin et al, 2010) andpressure-overload (McMullen et al, 2003) are worsened. Collectively, data to date reveal different dependencies of cardioprotection on PI3K vs. PI3K, and a paradoxical dependence of adenosine and ischaemic preconditioning responses on both EGFR transactivation and GPCR-sensitive PI3Kγ.…”

Section: Pi3kmentioning

confidence: 99%