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Overexpression of TGFβ1 by adeno-associated virus type-2 vector protects myocardium from ischemia–reperfusion injury

Gene Therapy volume 15, pages 415–423 (2008)Cite this article

Abstract

Transforming growth factor β1 (TGFβ1) has been purported to protect tissues from ischemia–reperfusion (I-R) injury. This study was designed to examine if overexpression of TGFβ1 using adeno-associated virus type 2 (AAV) protects cardiomyocytes from reoxygenation injury. TGFβ1 was overexpressed in cultured HL-1 mouse cardiomyocytes by transfection with AAV/TGFβ1Latent or with AAV/TGFβ1ACT (active TGFβ1). TGFβ1 upregulation reduced cardiomyocyte apoptosis and necrosis induced by 24 h of hypoxia followed by 3 h of reoxygenation concomitant with reduction in reactive oxygen species release, activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and NF-κB expression. Transfection with AAV/TGFβ1ACT was superior to that with AAV/TGFβ1Latent. To determine if AAV/TGFβ1ACT upregulation in vivo would induce cardioprotection from I-R injury, rat hearts were injected with AAV/TGFβ1ACT or phosphate-buffered saline (PBS). Six weeks later, TGFβ1ACT was upregulated throughout the myocardium. Following I-R, AAV/TGFβ1ACT-overexpressing rats had much smaller infarct size (P<0.01 vs PBS group), which was also related to reduced activation of NADPH oxidase and NF-κB, and lower levels of malondialdehyde in I-R tissues. These data demonstrate that overexpression of TGFβ1 by AAV can protect cardiac tissues from reperfusion injury, possibly via antioxidant mechanism. These findings suggest potential of TGFβ1ACT gene therapy for cardioprotection from I-R injury.

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Acknowledgements

This study was supported by a grant from the Department of Veterans Affairs and the National American Heart Association.

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Author notes

  1. A Dandapat and C P Hu: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Cardiology, Gene Therapy Program, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    A Dandapat, C P Hu, D Li, Y Liu, H Chen, P L Hermonat & J L Mehta

  2. Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China

    C P Hu

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  1. A Dandapat
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  2. C P Hu
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  4. Y Liu
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Correspondence to J L Mehta.

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Dandapat, A., Hu, C., Li, D. et al. Overexpression of TGFβ1 by adeno-associated virus type-2 vector protects myocardium from ischemia–reperfusion injury. Gene Ther 15, 415–423 (2008). https://doi.org/10.1038/sj.gt.3303071

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