Thioredoxin-1 gene delivery induces heme oxygenase-1 mediated myocardial preservation after chronic infarction in hypertensive rats.
BACKGROUND
Hypertension, the major risk factor for many cardiovascular diseases, is a result of multiple causes along with excessive generation of reactive oxygen species (ROS) resulting in imbalance of redox status.


METHODS
In this study, we investigated the therapeutic potential of Adenoviral-Thioredoxin-1 (Adeno-Trx-1) in spontaneous hypertensive rats (SHRs) at a dosage of 1 x 10(9) pfu. The rats were assigned as normotensive Wistar-Kyoto (WKY), SHR, SHR + Adeno-Lac-Z (SHRLac-Z), and SHR + Adeno-Trx-1 (SHRTrx-1). Echo-guided injection of adeno virus was done 48 h before permanent myocardial infarction (MI) by left anterior descending coronary artery (LAD) occlusion.


RESULTS
Decreased infarct size (52 +/- 4.1% vs. 67 +/- 6.1%), number of apoptotic cardiomyocytes (161 +/- 14.8 vs. 240 +/- 22.2), left ventricular inner diameter (7 +/- 0.33 vs. 9 +/- 0.46 mm), increased ejection fraction (52 +/- 6.3 vs. 42 +/- 3.3%), and fractional shortening (28 +/- 1.8 vs. 22 +/- 2.04 %) was observed in the SHRTrx-1 compared to SHR. Western Blot and immunohistochemical analysis demonstrated increased expression of Trx-1, HO-1, and Bcl-2 in the SHRTrx-1 compared to SHR. In addition, increased HO-1 activity was also observed in SHRTrx-1 as compared to SHR and SHRLac-Z groups.


CONCLUSIONS
Our study demonstrates that the cardioprotective effect of Adeno-Trx-1 gene therapy in SHR is Trx-1/HO-1/Bcl-2 mediated and may represent future target to develop therapy against hypertension associated cardiac failure.
Koneru
Srikanth
S
Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA.
Penumathsa
Suresh V
SV
Thirunavukkarasu
Mahesh
M
Zhan
Lijun
L
Maulik
Nilanjana
N
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004790:Enzyme Induction; D015316:Genetic Therapy; D006352:Heart Ventricles / Q000503:physiopathology; D051547:Heme Oxygenase-1 / Q000502:physiology*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013879:Thioredoxins / Q000235:genetics* / Q000627:therapeutic use*
D002316:Cardiotonic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013879:Thioredoxins; D051547:Heme Oxygenase-1