Basic Research - Infertility & Sexual Dysfunction(구연) (E-026) 당뇨성 발기부전 마우스에서 Cth-SDF1 pathway를 통한 Heat Shock Protein 70의 발기능 개선 효과 인하대학교 의과대학 비뇨의학교실, 인하대병원 성의학특성화센터 Ghatak Kalyan,윤국남, 최민지, 옥지연, 아니타, 권미혜, 서준규, 류지간 Introduction & Objective: Penile neurovascular dysfunction is a major cause of erectile dysfunction (ED) in patients with diabetes, which is responsible for poor response rate to oral phosphodiesterase-5 inhibitors. Heat shock protein 70 (Hsp70) is one of the molecular chaperones and play an indispensable role for the regulation of cell proliferation, survival, and angiogenesis. However, the role of Hsp70 in ED has not been studied yet. We aimed to explore the mechanisms by which Hsp70 induces penile neurovascular regeneration and restores erectile function in streptozotocin (STZ)-induced diabetic mouse. Methods: Eight-week-old C57BL/6 male mice were distributed into 5 experimental groups: controls, STZ-induced diabetic mice receiving repeated intracavernous injections of PBS (days -3 & 0; 20 μL), Hsp70 (days -3 & 0; 5 µg), lentivirus for cystathionine gamma-lyase (Cth; 1 × 104 IFU), or Hsp70 + Cth lentivirus. The erectile function was measured at 2 weeks after treatment by electrical stimulation of the cavernous nerve. Penis was then harvested for histological and biochemical studies. We also determined the efficacy of Hsp70 in primary cultured mouse cavernous endothelial cells (MCEC) in vitro and in ex vivo cultured major pelvic ganglion (MPG). Results: Intracavernous administration of Hsp70 restored erectile function in the diabetic mice, which reached up to 90% of control values. Hsp70 protein induced significant restoration of cavernous contents of endothelial cells, pericytes, and neuronal cells in the diabetic mice in vivo; promoted tube formation in primary cultured MCECs under high-glucose condition in vitro; and accelerated neurite sprouting from MPG under high-glucose condition ex vivo, by regulating the expression of neurotrophic factors (BDNF, NGF and NT-3). By using transcriptome analysis and cytokine array, we found that Cth and stromal cell-derived factor 1 (SDF1) is a major molecular target for HSP70-mediated angiogenesis and neural regeneration. Conclusion: Hsp70 significantly improved the erectile function through recovery of damaged penile blood vessels and nerves in diabetic condition through Cth-SDF1 pathway. The dual angiogenic and neurotrophic effects of Hsp70, especially local therapy in the form of therapeutic protein, will open a new avenue to treat diabetic ED. keywords : erectile dysfunction, diabetes mellitus, Hsp70