Functional recovery of diabetic mouse hearts by glutaredoxin-1 gene therapy: Role of Akt-FoxO-signaling network

I. Lekli, S. Mukherjee, D. Ray, N. Gurusamy, Y. H. Kim, A. Tósaki, R. M. Engelman, Y. S. Ho, D. K. Das

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Recent studies suggest that glutaredoxin-1 (Glrx-1) may serve as therapeutic target for diabetic hearts. As the level of reactive oxygen species (ROS) is increased in the pathologic hearts including ischemia/reperfusion (I/R) and diabetes, we assumed that upregulation of Glrx-1 could reduce the cardiac risk factors associated with I/R and/or diabetes. Diabetes was induced in mice by i.p. injection of streptozotocin (150 mg kg -1). Eight days after when the blood glucose was elevated to 400 mg per 100 ml, the animals were randomly assigned to one of the following three groups, which received either empty vector, or LacZ or Glrx-1 adenoviral construct. Four days later, isolated working hearts were subjected to 30 min ischemia followed by 2 h reperfusion. Glrx-1 gene therapy significantly enhanced the Glrx-1 level, which prevented I/R-mediated reduction of ventricular recovery, increased myocardial infarct size and cardiomyocyte apoptosis in diabetic myocardium. In concert, Glrx-1 prevented diabetes and ischemia-reperfusion induced reduction of cardioprotective proteins including Akt, FoxO-1, and hemeoxygenase-1, and abolished the death signal triggered by Jnk, p38 mitogen-activated protein kinase, and c-Src. Glrx-1 gene therapy seems to prevent cardiac complications in diabetic heart due to the I/R by switching the death signal into survival signal by activating Akt-FoxO-signaling network.

Original languageEnglish
Pages (from-to)478-485
Number of pages8
JournalGene Therapy
Volume17
Issue number4
DOIs
Publication statusPublished - Apr 2010

Fingerprint

Glutaredoxins
Genetic Therapy
Reperfusion
Ischemia
Heme Oxygenase-1
p38 Mitogen-Activated Protein Kinases
Diabetes Complications
Streptozocin
Cardiac Myocytes
Blood Glucose
Reactive Oxygen Species
Myocardium
Up-Regulation
Myocardial Infarction
Apoptosis
Injections

Keywords

  • AKT-FoxO-signaling network
  • Diabetes
  • Glrx-1 gene therapy
  • Glutaredoxin-1
  • Ischemia/reperfusion

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Functional recovery of diabetic mouse hearts by glutaredoxin-1 gene therapy : Role of Akt-FoxO-signaling network. / Lekli, I.; Mukherjee, S.; Ray, D.; Gurusamy, N.; Kim, Y. H.; Tósaki, A.; Engelman, R. M.; Ho, Y. S.; Das, D. K.

In: Gene Therapy, Vol. 17, No. 4, 04.2010, p. 478-485.

Research output: Contribution to journalArticle

Lekli, I, Mukherjee, S, Ray, D, Gurusamy, N, Kim, YH, Tósaki, A, Engelman, RM, Ho, YS & Das, DK 2010, 'Functional recovery of diabetic mouse hearts by glutaredoxin-1 gene therapy: Role of Akt-FoxO-signaling network', Gene Therapy, vol. 17, no. 4, pp. 478-485. https://doi.org/10.1038/gt.2010.9
Lekli, I. ; Mukherjee, S. ; Ray, D. ; Gurusamy, N. ; Kim, Y. H. ; Tósaki, A. ; Engelman, R. M. ; Ho, Y. S. ; Das, D. K. / Functional recovery of diabetic mouse hearts by glutaredoxin-1 gene therapy : Role of Akt-FoxO-signaling network. In: Gene Therapy. 2010 ; Vol. 17, No. 4. pp. 478-485.
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