Insulin suppresses ischemic preconditioning-mediated cardioprotection through Akt-dependent mechanisms

Tanner M Fullmer; Shaobo Pei; Yi Zhu; Crystal Sloan; Robert Manzanares; Brandon Henrie; Karla M Pires; James E Cox; E Dale Abel; Sihem Boudina

doi:10.1016/j.yjmcc.2013.08.005

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Insulin suppresses ischemic preconditioning-mediated cardioprotection through Akt-dependent mechanisms

Journal article

Open access

Peer reviewed

Insulin suppresses ischemic preconditioning-mediated cardioprotection through Akt-dependent mechanisms

Tanner M Fullmer, Shaobo Pei, Yi Zhu, Crystal Sloan, Robert Manzanares, Brandon Henrie, Karla M Pires, James E Cox, E Dale Abel and Sihem Boudina

Journal of molecular and cellular cardiology, Vol.64, pp.20-29

11/2013

DOI: 10.1016/j.yjmcc.2013.08.005

PMCID: PMC3835741

PMID: 23994159

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Abstract

It is believed that the diabetic myocardium is refractory to cardioprotection by ischemic preconditioning (IPC) mainly because of impaired insulin signaling to phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB or Akt). However, human as well as animal studies have clearly showed that the hearts of type 2 diabetic humans and animals may exhibit increased signaling through PI3K-Akt but yet are resistant to cardioprotection by IPC or ischemic post-conditioning. Therefore, this study was designed to determine whether activation of insulin signaling prior to IPC is detrimental for cardioprotection and to assess the role of insulin receptors (IRs) and Akt in mediating this effect. Wild-type (WT) hearts, hearts lacking IRs or hearts expressing an active form of Akt (myrAkt1) were perfused ex vivo using a Langendorff preparation and were subjected to IPC (3cycles of 5min ischemia followed by 5min reflow before 30min no flow ischemia and then by 45min reperfusion) in the presence or absence of 1nmol/L insulin. Interestingly, whereas insulin was protective against I/R (30min no flow ischemia and 45min reperfusion), it completely abolished cardioprotection by IPC in WT hearts but not in mice lacking insulin receptors (IRs) in cardiomyocytes (CIRKO) or in all cardiac cells (TIRKO). The suppression of IPC-mediated cardioprotection was mediated through downstream signaling to Akt and Gsk3β. In addition, transgenic induction of Akt in the heart was sufficient to abrogate IPC even when insulin was absent, further confirming the involvement of Akt in insulin's suppression of cardioprotection by IPC. These data provide evidence that excessive insulin signaling to Akt is detrimental for cardioprotection by IPC and could explain the failure of the diabetic myocardium to precondition.

Mitogen-Activated Protein Kinases

Insulin - pharmacology

Phosphorylation

Signal Transduction

Cardiotonic Agents - metabolism

Glycogen Synthase Kinase 3 beta

Male

Mice, Transgenic

Myocardium - pathology

Cardiotonic Agents - pharmacology

Glycogen Synthase Kinase 3 - metabolism

Mice, Knockout

Myocardial Reperfusion Injury - metabolism

Insulin - metabolism

Animals

Glycogen - metabolism

Ischemic Preconditioning, Myocardial

Myocardium - metabolism

Lactic Acid - biosynthesis

Receptor, Insulin - metabolism

Mice

Proto-Oncogene Proteins c-akt - metabolism

Myocardial Reperfusion Injury - genetics

Myocardial Reperfusion Injury - prevention & control

Details

Title: Subtitle: Insulin suppresses ischemic preconditioning-mediated cardioprotection through Akt-dependent mechanisms
Creators: Tanner M Fullmer - Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Shaobo Pei
Yi Zhu
Crystal Sloan
Robert Manzanares
Brandon Henrie
Karla M Pires
James E Cox
E Dale Abel
Sihem Boudina
Resource Type: Journal article
Publication Details: Journal of molecular and cellular cardiology, Vol.64, pp.20-29
DOI: 10.1016/j.yjmcc.2013.08.005
PMID: 23994159
PMCID: PMC3835741
NLM abbreviation: J Mol Cell Cardiol
ISSN: 0022-2828
eISSN: 1095-8584
Publisher: England
Grant note: R01DK092065 / NIDDK NIH HHS U01 HL087947 / NHLBI NIH HHS P30HL101310 / NHLBI NIH HHS
Language: English
Date published: 11/2013
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984025286302771

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