A Potential Role for PTEN in the Diabetic Heart

Mocanu, Mihaela M.; Field, Duncan C.; Yellon, Derek M.

doi:10.1007/s10557-006-8876-4

Cited by 24 publications

(15 citation statements)

References 10 publications

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“…However, it has been shown that preconditioning is less effective in limiting IS in diabetic animals due to higher levels of Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) that prevents effective Akt phosphorylation [31,50]. Here, we show that both VA and AL augmented Akt phosphorylation at Ser-473 and Thr-308 after ischemia-reperfusion, and that the levels of P-Akt were highest in the AL50+Va16 group, in agreement with their smallest IS.…”

Section: Akt Phosphorylationsupporting

confidence: 65%

“…Our findings that at 8 mg/kg/d, VA did not affect IS in Db/Db mice support the findings of Hotta and colleagues that animals with T2DM may be more resistant to preconditioning with ARBs than nondiabetic animals. Indeed, it has been shown that preconditioning is less effective in limiting IS in diabetic animals due to higher levels of Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) that prevents effective Akt phosphorylation [31,50]. However, we are showing that with a higher dose (16 mg/kg/d), VA effectively limited IS without a major blood pressure lowering effect in Db/Db mice.…”

Section: Valsartan and Myocardial Protection Against Ischemia-reperfumentioning

confidence: 75%

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Aliskiren and Valsartan Reduce Myocardial AT1 Receptor Expression and Limit Myocardial Infarct Size in Diabetic Mice

Qian

Castillo

et al. 2011

Cardiovasc Drugs Ther

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Section: Akt Phosphorylationsupporting

confidence: 65%

Section: Valsartan and Myocardial Protection Against Ischemia-reperfumentioning

confidence: 75%

Aliskiren and Valsartan Reduce Myocardial AT1 Receptor Expression and Limit Myocardial Infarct Size in Diabetic Mice

Qian

Castillo

et al. 2011

Cardiovasc Drugs Ther

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“…However, if activated chronically, PI3K/Akt has pro hypertrophic and pro oncogenic consequences and therefore this signaling kinase cascade is tightly controlled. The most important downregulator of this pathway is PTEN (phosphatase and tensin homologue on chromosome 10), which dephosphorylates the second messenger PtdIns [3,4,5] P3 resulting from PI3K activity, thus blocking Akt activation [3] and potentially having a negative impact upon myocardial survival following an ischaemic episode [4,5]. We have recently investigated the PTEN+/− mouse heart which is characterized by a decreased PTEN level and an increase in phosphorylated (therefore activated) Akt.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial PINK1—A Novel Cardioprotective Kinase?

Siddall

Warrell

Davidson

et al. 2008

Cardiovasc Drugs Ther

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“…Overexpression of PTEN increases apoptosis in neonatal cardiomyocytes, whereas expression of inactive mutant PTEN leads to Akt activation and reduces apoptosis (42). Moreover, myocardial levels of PTEN are increased in diabetic rats compared with nondiabetic rats, leading to reduced ability to phosphorylate Akt and, hence, blunting the protective effects of ischemic preconditioning (31,52). Only two studies (41,46) have assessed the effect of genetic deletion of PTEN on myocardial infarct size, both in an isolated heart model.…”

mentioning

confidence: 99%

Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia

Qian

Ling

Castillo

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Phosphatase and tensin homolog on chromosome 10 (PTEN) is downregulated during hypertrophic and cancerous cell growth, leading to activation of the prosurvival Akt pathway. However, PTEN regulation in cardiac myocytes upon exposure to hypoxia remains unclear. We explored the role of PTEN in response to hypoxia/ischemia in the myocardium. We validated that PTEN is a transcriptional target of activating transcription factor 2 (ATF-2) and is positively regulated via a p38/ATF-2 signaling pathway. Accordingly, hypoxia-induced upregulation of phosphorylation of ATF-2 and PTEN were reversed by a dominant negative mutant p38. Inhibition of PTEN in cardiomyocytes attenuated hypoxiainduced cell death and apoptosis. Cardiac-specific knockout of PTEN resulted in increased phosphorylation of Akt and forkhead box O 1 (forkhead transcription factors), limited infarct size in animals exposed to ischemia-reperfusion injury, and ameliorated deterioration of left ventricular function and remodeling following permanent coronary artery occlusion. In addition, the activation of Bim, FASL, and caspase was coupled with PTEN activation, all of which were attenuated by PTEN inhibition. In conclusion, cardiomyocyte-specific conditional PTEN deletion limited myocardial infarct size in an in vivo model of ischemia-reperfusion injury and attenuated adverse remodeling in a model of chronic permanent coronary artery ligation. p38; activating transcription factor 2; Akt; forkhead box O 1; FAS ligand; ischemia; infarct size; reperfusion PHOSPHOINOSITIDE 3-KINASE (PI3K) phosphorylates phosphatidylinositol, producing phosphatidylinositol (3,4,5)-triphosphate (PIP3), which recruits and facilitates activation of Akt (14, 32). Phosphatase and tensin homolog on chromosome 10 (PTEN) is a dual protein-lipid phosphatase that degrades PIP3 to inactive phosphatidylinositol (4,5)-diphosphate (PIP2; Refs. 22,26,38,47) and so negatively regulates the PI3K/Akt prosurvival signaling pathway. Loss or mutation of PTEN, with subsequent uncontrolled activation of the prosurvival pathways, is common in many tumors, including endometrial carcinoma, melanoma, renal, breast, prostate, and lung cancer (6, 9, 23). Dysregulation of PTEN has also been reported in heart diseases such as cardiac hypotrophy, heart failure, and ischemic heart disease (37,46,55,58). We (18) have shown that pharmacological inhibition of PTEN protects the heart against ischemiareperfusion injury through upregulation of the PI3K/Akt/endothelial nitric oxide synthase/ERK prosurvival pathway. Overexpression of PTEN increases apoptosis in neonatal cardiomyocytes, whereas expression of inactive mutant PTEN leads to Akt activation and reduces apoptosis (42). Moreover, myocardial levels of PTEN are increased in diabetic rats compared with nondiabetic rats, leading to reduced ability to phosphorylate Akt and, hence, blunting the protective effects of ischemic preconditioning (31, 52). Only two studies (41, 46) have assessed the effect of genetic deletion of PTEN on myocardial infarct size, both in an is...

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A Potential Role for PTEN in the Diabetic Heart

Cited by 24 publications

References 10 publications

Aliskiren and Valsartan Reduce Myocardial AT1 Receptor Expression and Limit Myocardial Infarct Size in Diabetic Mice

Aliskiren and Valsartan Reduce Myocardial AT1 Receptor Expression and Limit Myocardial Infarct Size in Diabetic Mice

Mitochondrial PINK1—A Novel Cardioprotective Kinase?

Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia

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