Role of LIM-kinase2 inhibition in Improvement of erectile function through suppression of corporal fibrosis in a rat model of cavernous nerve injury

Abstract

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).<br/> <br/> 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.<br/> <br/> 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.<br/> <br/> 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.