Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences.

Abstract

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.

• Authors: Qianhong Li, Yiru Guo, Wei Tan, Adam B Stein, Buddhadeb Dawn, Wen-Jian Wu, Xiaoping Zhu, Xiaoqin Lu, Xiaoming Xu, Tariq Siddiqui, Sumit Tiwari, Roberto Bolli
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 290 Issue 2 Pg. H584-9 (Feb 2006) ISSN: 0363-6135 [Print] United States
• PMID: 16172153 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cardiotonic Agents
• Nitric Oxide Synthase Type II

Topics

• Animals
• Cardiotonic Agents (metabolism)
• Echocardiography
• Gene Expression
• Genetic Therapy
• Heart (physiopathology)
• Male
• Mice
• Mice, Inbred ICR
• Myocardial Infarction (diagnostic imaging, pathology, physiopathology)
• Myocardium (enzymology, pathology)
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Time Factors