Thioredoxin-1 gene therapy enhances angiogenic signaling and reduces ventricular remodeling in infarcted myocardium of diabetic rats.

Samson Mathews Samuel, Mahesh Thirunavukkarasu, Suresh Varma Penumathsa, Srikanth Koneru, Lijun Zhan, Gautam Maulik, Perumana R. Sudhakaran, Nilanjana Maulik

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Abstract

BACKGROUND: The present study evaluated the reversal of diabetes-mediated impairment of angiogenesis in a myocardial infarction model of type 1 diabetic rats by intramyocardial administration of an adenoviral vector encoding thioredoxin-1 (Ad.Trx1). Various studies have linked diabetes-mediated impairment of angiogenesis to dysfunctional antioxidant systems in which thioredoxin-1 plays a central role. METHODS AND RESULTS: Ad.Trx1 was administered intramyocardially in nondiabetic and diabetic rats immediately after myocardial infarction. Ad.LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. Myocardial function was measured by echocardiography 30 days after the intervention. The Ad.Trx1-administered group exhibited reduced fibrosis, oxidative stress, and cardiomyocyte and endothelial cell apoptosis compared with the diabetic myocardial infarction group, along with increased capillary and arteriolar density. Western blot and immunohistochemical analysis demonstrated myocardial overexpression of thioredoxin-1, heme oxygenase-1, vascular endothelial growth factor, and p38 mitogen-activated protein kinase-beta, as well as decreased phosphorylated JNK and p38 mitogen-activated protein kinase-alpha, in the Ad.Trx1-treated diabetic group. Conversely, we observed a significant reduction in the expression of vascular endothelial growth factor in nondiabetic and diabetic animals treated with tin protoporphyrin (SnPP, a heme oxygenase-1 enzyme inhibitor), even after Ad.Trx1 therapy. Echocardiographic analysis after 4 weeks of myocardial infarction revealed significant improvement in myocardial functional parameters such as ejection fraction, fractional shortening, and E/A ratio in the Ad.Trx1-administered group compared with the diabetic myocardial infarction group. CONCLUSIONS: This study demonstrates for the first time that impairment of angiogenesis and myocardial dysfunction can be regulated by Ad.Trx1 gene therapy in streptozotocin-induced diabetic rats subjected to infarction.

Original languageEnglish
Pages (from-to)1244-1255
Number of pages12
JournalCirculation
Volume121
Issue number10
DOIs
Publication statusPublished - 16 Mar 2010
Externally publishedYes

Fingerprint

Thioredoxins
Ventricular Remodeling
Genetic Therapy
Myocardium
Myocardial Infarction
Heme Oxygenase-1
p38 Mitogen-Activated Protein Kinases
Vascular Endothelial Growth Factor A
JNK Mitogen-Activated Protein Kinases
Enzyme Inhibitors
Streptozocin
Cardiac Myocytes
Infarction
Echocardiography
Oxidative Stress
Fibrosis
Endothelial Cells
Antioxidants
Western Blotting
Apoptosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Thioredoxin-1 gene therapy enhances angiogenic signaling and reduces ventricular remodeling in infarcted myocardium of diabetic rats. / Mathews Samuel, Samson; Thirunavukkarasu, Mahesh; Penumathsa, Suresh Varma; Koneru, Srikanth; Zhan, Lijun; Maulik, Gautam; Sudhakaran, Perumana R.; Maulik, Nilanjana.

In: Circulation, Vol. 121, No. 10, 16.03.2010, p. 1244-1255.

Research output: Contribution to journalArticle

Mathews Samuel, S, Thirunavukkarasu, M, Penumathsa, SV, Koneru, S, Zhan, L, Maulik, G, Sudhakaran, PR & Maulik, N 2010, 'Thioredoxin-1 gene therapy enhances angiogenic signaling and reduces ventricular remodeling in infarcted myocardium of diabetic rats.', Circulation, vol. 121, no. 10, pp. 1244-1255. https://doi.org/10.1161/CIRCULATIONAHA.109.872481
Mathews Samuel, Samson ; Thirunavukkarasu, Mahesh ; Penumathsa, Suresh Varma ; Koneru, Srikanth ; Zhan, Lijun ; Maulik, Gautam ; Sudhakaran, Perumana R. ; Maulik, Nilanjana. / Thioredoxin-1 gene therapy enhances angiogenic signaling and reduces ventricular remodeling in infarcted myocardium of diabetic rats. In: Circulation. 2010 ; Vol. 121, No. 10. pp. 1244-1255.
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AU - Thirunavukkarasu, Mahesh

AU - Penumathsa, Suresh Varma

AU - Koneru, Srikanth

AU - Zhan, Lijun

AU - Maulik, Gautam

AU - Sudhakaran, Perumana R.

AU - Maulik, Nilanjana

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