2016
DOI: 10.18632/aging.100933
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Abstract: Insulin protects cardiomyocytes from myocardial ischemia/reperfusion (MI/R) injury through activating Akt. However, phosphatase PHLPP-1 (PH domain leucine-rich repeat protein phosphatase-1) dephosphorylates and inactivates Akt. The balanced competitive interaction of insulin and PHLPP-1 has not been directly examined. In this study, we have identified the effect of mutual inhibition of insulin signaling and PHLPP-1 on the cardioprotective efficiency of Akt in aged heart. Young (3 mon) and aged (20 mon) Sprague… Show more

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Cited by 26 publications
(22 citation statements)
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References 39 publications
(63 reference statements)
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“…Knockout of PHLPP-1 potentiated Akt phosphorylation at Ser473 and reduced infarct size in response to I/R challenge [43]. A most recent study revealed that PHLPP-1 expression is increased with aging, and an increase in PHLPP-1 expression exacerbated hypoxia/reoxygenation-induced apoptosis [44]. Similarly, Akt can also be dephosphorylated by PHLPP-2, which is activated by isoproterenol and forskolin through a cyclic AMP- (cAMP-) independent mechanism [45].…”
Section: Pi3k/akt Pathwaymentioning
confidence: 99%
“…Knockout of PHLPP-1 potentiated Akt phosphorylation at Ser473 and reduced infarct size in response to I/R challenge [43]. A most recent study revealed that PHLPP-1 expression is increased with aging, and an increase in PHLPP-1 expression exacerbated hypoxia/reoxygenation-induced apoptosis [44]. Similarly, Akt can also be dephosphorylated by PHLPP-2, which is activated by isoproterenol and forskolin through a cyclic AMP- (cAMP-) independent mechanism [45].…”
Section: Pi3k/akt Pathwaymentioning
confidence: 99%
“…Further, liver and skeletal muscle cells transfected with recombinant PHLPP1 demonstrated decreased GSK-3α/β phosphorylation and glycogen synthesis confirming the fact that changes in PHLPP1 abundance contribute to insulin resistance (Aviv & Kirshenbaum 2010). Recently proposed mechanism suggests that insulin suppresses PHLPP1 to enhance AKT activation but as lower insulin effectiveness prevails in aged hearts, it fails to decrease PHLPP1 during myocardial infarction/reperfusion, subsequently limiting AKT activity and cardioprotection (Xing et al 2016). One of the studies in obese mice confirmed that increased PHLPP1 expression allows pronounced AKT/PHLPP1 interaction which weakens the insulin response (Caricilli et al 2012) and hypothalamic silencing of PHLPP1 lead to greater weight loss and reduction in adiposity with improved insulin signaling in obese mice (Caricilli et al 2012).…”
Section: :3mentioning
confidence: 79%
“…Interestingly, during diabetes, inhibition in PI3K/AKT signaling prevents docking of bTrCP to PHLPP1 leading to sustained activation of PHLPP (Warfarel et al 2011). A very recent study identified that insulin regulates PHLPP1 degradation in cardiomyocytes (Xing et al 2016). Low insulin effectiveness prevails in aged hearts, which subsequently fail to decrease PHLPP1 during MI/R (myocardial ischemia/reperfusion) and thereby limits AKT activity and cardioprotection.…”
Section: Figurementioning
confidence: 99%
“…However, PHLPP-1 knockdown or enhanced insulin sensitivity dramatically increased the phosphorylation of Akt and restored insulin induced cardioprotection (27). Taken together, it is an indisputable fact that aging is associated with the loss or attenuation of conditioning protection.…”
Section: Agingmentioning
confidence: 96%
“…was due to few extra Akt activation resulting from chronic Akt phosphorylation in the baseline, and continuous overexpression of Akt resulted in contractile dysfunction and susceptibility to cardiac injury (26). On the contrary, aging suppressed the conditioning protection due to insulin insensitiveness and overexpression of PHLPP-1(a specific negative regulator of Akt) during myocardial IRI, which subsequently limited Akt activity in the aged heart (27). In addition, a new study reported that ischemic postconditioning (IPostC) failed to exert its cardioprotective effect owing to thioredoxin-1 degradation, a part of antioxidant system, and subsequently inactivated the Akt and GSK3β in middle-aged and old animals (28).…”
Section: Agingmentioning
confidence: 99%