title: Mutual inhibition of insulin signaling and PHLPP-1 determines cardioprotective efficiency of Akt in aged heart.
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 months) and aged (20 months) Sprague Dawley (SD) rats were subjected to MI/Rin vivo. The PHLPP-1 level was higher in aged vs. young hearts at base. But, insulin treatment failed to decrease PHLPP-1 level during reperfusion in the aged hearts. Consequently, the cardioprotection of insulin-induced Akt activation was impaired in aged hearts, resulting in more susceptible to MI/R injury. In cultured rat ventricular myocytes, PHLPP-1 knockdown significantly enhanced insulin-induced Akt phosphorylation and reduced simulated hypoxia/reoxygenation-induced apoptosis. Contrary, PHLPP-1 overexpression terminated Akt phosphorylation and deteriorated myocytes apoptosis. Using in vivo aged animal models, we confirmed that cardiac PHLPP-1 knockdown or enhanced insulin sensitivity by exercise training dramatically increased insulin-induced Akt phosphorylation. Specifically, MI/R-induced cardiomyocyte apoptosis and infarct size were decreased and cardiac function was increased. More importantly, we found that insulin regulated the degradation of PHLPP-1 and insulin treatment could enhance the binding between PHLPP-1 and β-transducin repeat-containing protein (β-TrCP) to target for ubiquitin-dependent degradation. Altogether, we have identified a new mechanism by which insulin suppresses PHLPP-1 to enhance Akt activation. But, aged heart possesses lower insulin effectiveness and fails to decrease PHLPP-1 during MI/R, which subsequently limited Akt activity and cardioprotection. PHLPP-1 could be a promising therapeutic interventional target for elderly ischemic heart disease patients.
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Jilin University, Changchun 130000, China.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yishi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an 710032, China.|Department of Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D007328:Insulin; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; C553451:PHLPP1 protein, rat
keywords: Akt; PHLPP-1; degradation; insulin; myocardial I/R