Abstract 1609: Cardiac-Specific Overexpression of Inducible Nitric Oxide Synthase Has A Potent Cardioprotective Effect in Both Young and Aged Mice
Previous studies have shown that gene therapy with inducible nitric oxide synthase (iNOS) protects against myocardial infarction (MI) at 2 months after gene transfer. However, the long-term effects of iNOS overexpression on acute MI and the impact of age are currently unknown. Accordingly, we studied the effect of age (young vs. old) on ischemia/reperfusion injury in transgenic mice with cardiac-specific overexpression of iNOS (iNOS-Tg). Young adult iNOS-Tg (16 ±1 wks, n=12), old iNOS-Tg (83 ± 3 wks, n=10), young adult wild-type (WT, 18 ± 3 wks, n=14), and old WT (78 ± 0 wks, n=7) mice were subjected to a 30-min coronary occlusion and 24 h of reperfusion. In young adult WT mice (group I), infarct size averaged 55.7 ± 3.7% of the risk region (Figure⇓). In old WT mice (group III), infarct size was slightly smaller (42.8 ± 3.5%) than in the young adult mice, indicating that age does not have a major impact on infarct size. When young adult iNOS-Tg mice were subjected to the same infarction protocol (group II), infarct size was much smaller (28.5 ± 3.6%), indicating that overexpression of the iNOS gene has a potent cardioprotective effect. When old iNOS-Tg mice were infarcted (group IV), infarct size was also significantly reduced (20.3 ± 3.3%). We conclude that selective cardiac-specific overexpression of iNOS induces a potent cardioprotective effect against MI in both young and old mice, implying that increased iNOS expression remains protective even after 16 months. The concept that iNOS is chronically protective has important therapeutic implications for studies of long-term gene therapy aimed at increasing myocardial iNOS content as well as for other iNOS-based strategies.