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


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.
Samuel
Samson Mathews
SM
Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030-1110, USA.
Thirunavukkarasu
Mahesh
M
Penumathsa
Suresh Varma
SV
Koneru
Srikanth
S
Zhan
Lijun
L
Maulik
Gautam
G
Sudhakaran
Perumana R
PR
Maulik
Nilanjana
N
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D042783:Endothelial Cells / Q000378:metabolism; D005355:Fibrosis; D015316:Genetic Therapy; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000032:analysis; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013311:Streptozocin; D013879:Thioredoxins / Q000032:analysis / Q000235:genetics*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis
D042461:Vascular Endothelial Growth Factor A; D013879:Thioredoxins; D013311:Streptozocin; D051547:Heme Oxygenase-1; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases