Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences.
Previous studies have shown that gene therapy with inducible nitric oxide synthase (iNOS) protects against myocardial infarction at 3 days after gene transfer. However, the long-term effects of iNOS gene therapy on myocardial ischemic injury and cardiac function are unknown. To address this issue, we used a recombinant adenovirus 5 (Ad5) vector (Av3) with deletions of the E1, E2a, and E3 regions, which enables long-lasting recombinant gene expression for at least 2 mo due to lack of inflammation. Mice received intramyocardial injections in the left ventricular (LV) anterior wall of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 1 or 2 mo later, they were subjected to myocardial infarction (30-min coronary occlusion followed by 4 h of reperfusion). Cardiac iNOS gene expression was confirmed by immunoblotting and activity assays at 1 and 2 mo after gene transfer. In the iNOS group, infarct size (percentage of risk region) was significantly reduced (P < 0.05) both at 1 mo (24.2 +/- 3.4%, n = 6, vs. 48.0 +/- 3.6%, n = 8, in the LacZ group) and at 2 mo (23.4 +/- 3.1%, n = 8, vs. 36.6 +/- 2.4%, n = 7). The infarct-sparing effects of iNOS gene therapy were as powerful as those observed 24 h after ischemic preconditioning (23.1 +/- 3.4%, n = 10). iNOS gene transfer had no effect on LV function or dimensions up to 8 wk later (echocardiography). These data demonstrate that iNOS gene therapy mediated by the Av3 vector affords long-term (2 mo) cardioprotection without inflammation or adverse functional consequences, a finding that provides a rationale for further preclinical testing of this therapy.
Li
Qianhong
Q
Institute of Molecular Cardiology, Univ. of Louisville, Louisville, KY, USA.
Guo
Yiru
Y
Tan
Wei
W
Stein
Adam B
AB
Dawn
Buddhadeb
B
Wu
Wen-Jian
WJ
Zhu
Xiaoping
X
Lu
Xiaoqin
X
Xu
Xiaoming
X
Siddiqui
Tariq
T
Tiwari
Sumit
S
Bolli
Roberto
R
D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D004452:Echocardiography; D015870:Gene Expression; D015316:Genetic Therapy; D006321:Heart / Q000503:physiopathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
D002316:Cardiotonic Agents; D052247:Nitric Oxide Synthase Type II