Abstract 5040: Antioxidative Treatment in Salt Loaded Zucker Diabetic Fatty Rats Prevents Vascular Hypertrophy
Vascular hypertrophy of resistance arteries is an early form of end-organ damage. In this study we test whether antioxidative treatment by inhibition of distinct sources of oxidative stress (namely NADPH oxidase and mitochondria) improves vascular remodeling and thereby reduces end-organ damage in diabetes mellitus (DM) associated with salt sensitive hypertension. As a model of type 2 DM Zucker Diabetic Fatty (ZDF) rats receiving high salt (5.5%) diet were divided into 3 groups receiving no antioxidative treatment (ZDF+S) or treated with inhibitors of sources of oxidative stress with apocynin (inhibitor of the NADPH oxidase) (ZDF+S+A) or with PJ-34 (PARP-inhibitor) (ZDF+S+PJ) for 6 weeks. Euglycemic Zucker lean (ZDL) rats served as controls. Systolic blood pressure (SBP) was measured weekly by tail cuff method. MRNA expressions of p22phox as a subunit of NADPH oxidase were quantified by RT-qPCR in mesenteric resistance arteries. Vascular hypertrophy (media to lumen ratio, M:L) and passive mechanical stiffness of mesenteric resistance arteries were assessed using a pressurized myograph. SBP was significantly higher in ZDF+S compared to ZDL (ZDF+S: 144±1; ZDL: 134±3 mmHg; p<0.05). There was no relative effect of antioxidative treatment on serum glucose levels and SBP (ZDF+S+A: 142±1; ZDF+S+PJ: 145±2 mmHg). M:L of mesenteric arteries was significantly increased in ZDF+S vs ZDL (5.8±0.3 vs 4.7±0.1; p<0.05) indicating marked vascular hypertrophy. Antioxidative treatment significantly prevented vascular hypertrophy by inhibition of NADPH oxidase with apocynin (M:L in ZDF+S+A: 4.4±0.2; p<0.05 vs ZDF+S) and by PARP-inhibition with PJ-34 (M:L in ZDF+S+PJ: 4.5±0.1; p<0.05 vs ZDF+S). Levels of p22phox were increased in ZDF+S vs ZDL (1.7±0.2 vs 1.3±0.2). Antioxidative treatment decreased the expression of p22phox (ZDF+S+A: 1.3±0.1; ZDF+S+PJ: 1.4±0.1). Antioxidative treatment did not change vascular strain indicating no effect on vascular stiffness. Antioxidative treatment with an inhibitor of NADPH oxidase and with a PARP-inhibitor prevented vascular hypertrophy in salt loaded ZDF rats without changing blood pressure levels. Thus, targeted inhibition of sources of oxidative stress may be of importance to prevent end-organ damage in diabetes.