Gene transfer of the inducible nos inhibits intimal hyperplasia in a model of diabetic vascular injury

Abstract

Introduction: Cardiovascular complications of diabetes contribute significantly to the morbidity of this disease. Intimal hyperplasia (IH), which limits our current therapies, is a disease process which disproportionately affects patients with diabetes. The pathophysiology of diabetic vascular disease may be, in part, secondary to decreased bioavailability of nitric oxide (NO). The purpose of these experiments was to test the hypothesis that gene transfer of inducible NO synthase (iNOS) prevents IH following balloon injury in a rodent model of diabetes. Methods: Obese Zucker rats were utilized as a model of Type II Diabetes. These rats carry a homozygous recessive gene (fa/fa) making them resistant to leptin. Their lean counterparts (fa/-) are leptin-sensitive and were used as controls. The obese rats underwent carotid artery balloon injury followed by either adenoviral iNOS or lacZ gene transfer at the time of injury (2x106 PFU per artery). The animals were sacrificed at 3, 7, and 21 days and the degree of injury assessed. Glucose, cholesterol, and insulin levels were also checked. Values are expressed as mean ± standard error and statistical analysis was performed using one-way ANOVA. Results: The obese Zucker rats had marked elevations in baseline glucose, cholesterol, and serum insulin levels compared to lean controls. IH was worse in obese rats compared to controls, with intima:media ratios (I:M) of 0.90 ± 0.14 vs 0.54 ± 0.08, respectively, at 21 days. AdlacZ treatment did not significantly affect the development of IH compared to untreated controls in both lean and obese rats. Adenoviral iNOS gene transfer significantly reduced IH by 37% in lean and 64% in obese rats, with I:M ratios of 0.34 ± 0.03 and 0.33 ± 0.07, respectively. Conclusion: Vascular injury resulted in greater IH in diabetic rodents, raising the concern that diabetes might also reduce the efficacy of therapies that have been shown to inhibit IH in normal animals. Adenoviral iNOS gene transfer effectively inhibits the formation of IH in control rats. The presence of diabetes did not reduce the efficacy of this treatment. Instead, iNOS gene transfer had a greater protective effect in obese diabetic Zucker rats. iNOS gene transfer may be a useful clinical adjunct to vascular interventions in diabetic patients.