S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
Role of LIM-kinase2 inhibition in Improvement of erectile function through suppression of corporal fibrosis in a rat model of cavernous nerve injury : 해면체 신경 손상 발기부전 백서 모델에서 LIMK2 억제제의 음경해면체 섬유화 차단 효과를 통한 발기력의 호전
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의학과, 2018. 8. 김수웅.
- Purpose: To determine whether LIM-kinase2 inhibitors (LIMK2i) could improve erectile function by suppression of corporal fibrosis through normalization of ROCK1/LIMK2/Cofilin pathway in a rat model of CN crush injury (CNCI).
Materials and Methods: Sixty 10-week-old male Sprague-Dawley rats were divided equally into five groups: sham surgery (S), CNCI (I), and CNCI treated with low-dose (L), medium-dose (M) and high-dose (H) LIMK2i. The L, M and H groups was treated with daily intraperitoneal injection of LIMK2i (2.5, 5.0 and 10.0 mg/kg, respectively) for 1-week from the following day after surgery. Erectile response was assessed using electrostimulation at 1-week postoperatively. Penile tissue was processed for Massons trichrome staining, double immunofluorescence and Western blotting.
Results: The I group showed significantly lower intracavernous pressure (ICP)/mean arterial pressure (MAP) and lower area under the curve (AUC)/MAP than the S group. The erectile responses in the H group improved compared to the I group, while the M group showed only partial improvements. Significantly decreased smooth muscle/collagen ratio and increased content of fibroblasts positive for phospho-LIMK2 were noted in the I group. The I group showed the increase in ROCK1 protein expression, LIMK2 phosphorylation and Cofilin phosphorylation. The M and H groups showed significant improvements in the histological alterations and the dysregulated LIMK2/Cofilin pathway, except for LIMK2 phosphorylation in the M group. The LIMK2 inhibition did not affect the ROCK1 protein expression. The content of fibroblasts positive for phospho-LIMK2 in the H group returned to the level found in the S group, while it did not in the M group. However, the L group did not show their improvements.
Conclusions: Our data suggest that inhibition of LIMK2, particularly with administration of 10.0 mg/kg LIMK2i, can improve corporal fibrosis and erectile function by normalizing LIMK2/Cofilin pathway.
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