MP89-19 ALTERED CAVEOLIN EXPRESSION IN DIABETIC PENIS: POSSIBLE ROLE IN ERECTILE DYSFUNCTION

INTRODUCTION AND OBJECTIVES: Pathophysiology of increased severity of erectile dysfunction (ED) in diabetic men and their poor response to phosphodiesterase 5 (PDE5) inhibitors are unclear. A defective vascular endothelium and consequent impairment in formation and/or action of nitric oxide (NO) are implicated as possible causes. Endothelial NO synthase (eNOS) is localized to caveolae (plasma membrane lipid rafts). Caveolins (Cav), structural components of caveolae, are recognized to play a regulatory role in the vascular complications of diabetes. Our objectives are to: (i) evaluate changes in Cav-1 and Cav-3 expression in penile tissue of type 2 diabetes (T2DM) mice and (ii) measure impact of Cav-1 deletion on penile PDE5 activity. METHODS: We used wild type C57BL6, Cav-1 and Cav-3 KO male mice (n1⁄46 each). To create T2DM mouse model, C57BL6 (15-18 months) male mice were injected with a single dose streptozotocin (non-fasted, 75 mg/kg i.p.) and switched to high fat diet (HFD; 60% kcal of total calories). Two months after HFD, serum glucose and GTT (glucose tolerance test) were performed to confirm metabolic disorder. Animals were maintained on HFD for 4 months and euthanized to harvest penile tissues. Expression levels of Cav-1 and Cav-3 were determined by Western blot and PDE5 activity was measured using [3H]cGMP as the substrate. RESULTS: A significant increase in body weight and impairment in GTT were observed in HFD-fed mice (Fig 1). A significant decrease in both Cav-1 and Cav-3 levels were observed in T2DM mice (D1-3) compared to WT mice (C1-2; Fig 2A). Stimulation of PDE5 activity in response to NO donor, GSNO was significantly higher (~2 fold) in Cav1KO (Fig 2B) compared to WT mice. CONCLUSIONS: Altered penile Cav-1 levels in T2DM mice and increased PDE5 activity after Cav-1 depletion suggests a regulatory role for Cav-1 in diabetes related ED. Targeting caveolins may be a novel approach to improve pharmacotherapeutic response in T2DM patients.