Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo

Takashi Matsui, Jingzang Tao, Federica Del Monte, Kyung Han Lee, Ling Li, Michael Picard, Thomas L. Force, Thomas F. Franke, Roger J. Hajjar, Anthony Rosenzweig

Research output: Contribution to journalArticlepeer-review

612 Scopus citations

Abstract

Background - The serine-threonine kinase Akt is activated by several ligand-receptor systems previously shown to be cardioprotective. Akt activation reduces cardiomyocyte apoptosis in models of transient ischemia. Its role in cardiac dysfunction or infarction, however, remains unclear. Methods and Results - We examined the effects of a constitutively active Akt mutant (myr-Akt) in a rat model of cardiac ischemia-reperfusion injury. In vivo gene transfer of myr-Akt reduced infarct size by 64% and the number of apoptotic cells by 84% (P<0.005 for each). Ischemia-reperfusion injury decreased regional cardiac wall thickening as well as the maximal rate of left ventricular pressure rise and fall (+dP/dt and -dP/dt). Akt activation restored regional wall thickening and +dP/dt and -dP/dt to levels seen in sham-operated rats. To better understand this benefit, we examined the effects of myr-Akt on hypoxic cardiomyocyte dysfunction in vitro. myr-Akt prevented hypoxia-induced abnormalities in cardiomyocyte calcium transients and shortening. Akt activation also enhanced sarcolemmal expression of Glut-4 in vivo and increased glucose uptake in vitro to the level seen with insulin treatment. Conclusions - Akt activation exerts a powerful cardioprotective effect after transient ischemia that probably reflects its ability to both inhibit cardiomyocyte death and improve function of surviving cardiomyocytes. Akt may represent an important nodal target for therapy in ischemic and other heart disease.

Original languageEnglish
Pages (from-to)330-335
Number of pages6
JournalCirculation
Volume104
Issue number3
DOIs
StatePublished - 17 Jul 2001
Externally publishedYes

Keywords

  • Apoptosis
  • Gene therapy
  • Ischemia
  • Signal transduction

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