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

Research output: Contribution to journalArticle

23 Scopus citations

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 (3. cycles of 5. min ischemia followed by 5. min reflow before 30. min no flow ischemia and then by 45. min reperfusion) in the presence or absence of 1. nmol/L insulin. Interestingly, whereas insulin was protective against I/R (30. min no flow ischemia and 45. min 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.

Original languageEnglish (US)
Pages (from-to)20-29
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume64
DOIs
StatePublished - Nov 1 2013

Keywords

  • Cardioprotection
  • Insulin
  • Insulin signaling
  • Ischemia
  • Reperfusion

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Fullmer, T. M., Pei, S., Zhu, Y., Sloan, C., Manzanares, R., Henrie, B., Pires, K. M., Cox, J. E., Abel, E. D., & Boudina, S. (2013). Insulin suppresses ischemic preconditioning-mediated cardioprotection through Akt-dependent mechanisms. Journal of Molecular and Cellular Cardiology, 64, 20-29. https://doi.org/10.1016/j.yjmcc.2013.08.005