Combination of LIM-kinase 2 and Jun Amino-terminal Kinase Inhibitors Improves Erectile Function in a Rat Model of Cavernous Nerve Injury

Soo Woong Kim, Junghoon Lee, Juhyun Park, Ji Sun Chai, Sohee Oh, Jae Seung Paick, Min Chul Cho

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective: To determine if combined administration of LIMK2 and JNK inhibitors in a rat model of erectile dysfunction induced by cavernosal nerve (CN) injury could restore erectile function by suppressing both cavernosal apoptosis and fibrosis via rectification of molecular pathways related to the structural alterations. Methods: Sixty 12-week-old male Sprague-Dawley rats were categorized into 4 groups: (1) Sham-surgery (Sham) group, (2) CN-crush-injury (CNCI), (3) CNCI group (CNCI+L+1.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and low-dose (1.0 mg/kg) JNK-inhibitors, and (4) CNCI group (CNCI+L+10.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and a high dose (10.0 mg/kg) of JNK-inhibitors. Ten days after surgery, erectile response, histological-studies, and Western-blot was investigated. Results: The CNCI group showed a reduced maximal ICP/MAP or AUC/MAP, decreased immunohistochemical-staining of α-SMA, decreased SM/collagen ratio, increased phospho-cJun-positive apoptotic cells, increased phospho-LIMK2-positive fibroblasts, increased cJun-phosphorylation, increased LIMK2/Cofilin-phosphorylation, decreased Bcl-2/Bax ratio, and increased protein-expression of fibronectin, compared to the Sham group. Both the CNCI+L+1.0J and CNCI+L+10.0J groups showed improvements in erectile-responses, content of cavernosal α-SMA, number of phospho-cJun-positive apoptotic cells, Bcl-2/Bax ratio and cJun phosphorylation. Their improvements in the CNCI+L+10.0J group showed a tendency to be greater than those in the CNCI+L+1.0J group. Also, in the 2 treatment groups, rectification of SM/collagen ratio, number of phospho-LIMK2-positive fibroblasts, LIMK2/Cofilin-phosphorylation, and protein-expression of fibronectin was observed. Conclusion: This study suggests that combined inhibition of JNK and LIMK2 may improve erectile function by suppressing cavernosal apoptosis and fibrosis via restoration of cJun/Bcl-2/Bax and LIMK2/Cofilin pathways at 10 days after CN injury.

Original languageEnglish
Pages (from-to)136-143
Number of pages8
JournalUrology
Volume131
DOIs
StatePublished - 1 Sep 2019

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Lim Kinases
MAP Kinase Kinase 4
Wounds and Injuries
Actin Depolymerizing Factors
Phosphorylation
Fibronectins
Fibrosis
Collagen
Fibroblasts
Crush Injuries
Apoptosis
Nerve Crush
Erectile Dysfunction
Ambulatory Surgical Procedures
Area Under Curve
Sprague Dawley Rats

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Kim, Soo Woong ; Lee, Junghoon ; Park, Juhyun ; Chai, Ji Sun ; Oh, Sohee ; Paick, Jae Seung ; Cho, Min Chul. / Combination of LIM-kinase 2 and Jun Amino-terminal Kinase Inhibitors Improves Erectile Function in a Rat Model of Cavernous Nerve Injury. In: Urology. 2019 ; Vol. 131. pp. 136-143.
@article{b0838b0406b44c81ade6de36f6b9acf3,
title = "Combination of LIM-kinase 2 and Jun Amino-terminal Kinase Inhibitors Improves Erectile Function in a Rat Model of Cavernous Nerve Injury",
abstract = "Objective: To determine if combined administration of LIMK2 and JNK inhibitors in a rat model of erectile dysfunction induced by cavernosal nerve (CN) injury could restore erectile function by suppressing both cavernosal apoptosis and fibrosis via rectification of molecular pathways related to the structural alterations. Methods: Sixty 12-week-old male Sprague-Dawley rats were categorized into 4 groups: (1) Sham-surgery (Sham) group, (2) CN-crush-injury (CNCI), (3) CNCI group (CNCI+L+1.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and low-dose (1.0 mg/kg) JNK-inhibitors, and (4) CNCI group (CNCI+L+10.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and a high dose (10.0 mg/kg) of JNK-inhibitors. Ten days after surgery, erectile response, histological-studies, and Western-blot was investigated. Results: The CNCI group showed a reduced maximal ICP/MAP or AUC/MAP, decreased immunohistochemical-staining of α-SMA, decreased SM/collagen ratio, increased phospho-cJun-positive apoptotic cells, increased phospho-LIMK2-positive fibroblasts, increased cJun-phosphorylation, increased LIMK2/Cofilin-phosphorylation, decreased Bcl-2/Bax ratio, and increased protein-expression of fibronectin, compared to the Sham group. Both the CNCI+L+1.0J and CNCI+L+10.0J groups showed improvements in erectile-responses, content of cavernosal α-SMA, number of phospho-cJun-positive apoptotic cells, Bcl-2/Bax ratio and cJun phosphorylation. Their improvements in the CNCI+L+10.0J group showed a tendency to be greater than those in the CNCI+L+1.0J group. Also, in the 2 treatment groups, rectification of SM/collagen ratio, number of phospho-LIMK2-positive fibroblasts, LIMK2/Cofilin-phosphorylation, and protein-expression of fibronectin was observed. Conclusion: This study suggests that combined inhibition of JNK and LIMK2 may improve erectile function by suppressing cavernosal apoptosis and fibrosis via restoration of cJun/Bcl-2/Bax and LIMK2/Cofilin pathways at 10 days after CN injury.",
author = "Kim, {Soo Woong} and Junghoon Lee and Juhyun Park and Chai, {Ji Sun} and Sohee Oh and Paick, {Jae Seung} and Cho, {Min Chul}",
year = "2019",
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language = "English",
volume = "131",
pages = "136--143",
journal = "Urology",
issn = "0090-4295",
publisher = "Elsevier Inc.",

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Combination of LIM-kinase 2 and Jun Amino-terminal Kinase Inhibitors Improves Erectile Function in a Rat Model of Cavernous Nerve Injury. / Kim, Soo Woong; Lee, Junghoon; Park, Juhyun; Chai, Ji Sun; Oh, Sohee; Paick, Jae Seung; Cho, Min Chul.

In: Urology, Vol. 131, 01.09.2019, p. 136-143.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Combination of LIM-kinase 2 and Jun Amino-terminal Kinase Inhibitors Improves Erectile Function in a Rat Model of Cavernous Nerve Injury

AU - Kim, Soo Woong

AU - Lee, Junghoon

AU - Park, Juhyun

AU - Chai, Ji Sun

AU - Oh, Sohee

AU - Paick, Jae Seung

AU - Cho, Min Chul

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Objective: To determine if combined administration of LIMK2 and JNK inhibitors in a rat model of erectile dysfunction induced by cavernosal nerve (CN) injury could restore erectile function by suppressing both cavernosal apoptosis and fibrosis via rectification of molecular pathways related to the structural alterations. Methods: Sixty 12-week-old male Sprague-Dawley rats were categorized into 4 groups: (1) Sham-surgery (Sham) group, (2) CN-crush-injury (CNCI), (3) CNCI group (CNCI+L+1.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and low-dose (1.0 mg/kg) JNK-inhibitors, and (4) CNCI group (CNCI+L+10.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and a high dose (10.0 mg/kg) of JNK-inhibitors. Ten days after surgery, erectile response, histological-studies, and Western-blot was investigated. Results: The CNCI group showed a reduced maximal ICP/MAP or AUC/MAP, decreased immunohistochemical-staining of α-SMA, decreased SM/collagen ratio, increased phospho-cJun-positive apoptotic cells, increased phospho-LIMK2-positive fibroblasts, increased cJun-phosphorylation, increased LIMK2/Cofilin-phosphorylation, decreased Bcl-2/Bax ratio, and increased protein-expression of fibronectin, compared to the Sham group. Both the CNCI+L+1.0J and CNCI+L+10.0J groups showed improvements in erectile-responses, content of cavernosal α-SMA, number of phospho-cJun-positive apoptotic cells, Bcl-2/Bax ratio and cJun phosphorylation. Their improvements in the CNCI+L+10.0J group showed a tendency to be greater than those in the CNCI+L+1.0J group. Also, in the 2 treatment groups, rectification of SM/collagen ratio, number of phospho-LIMK2-positive fibroblasts, LIMK2/Cofilin-phosphorylation, and protein-expression of fibronectin was observed. Conclusion: This study suggests that combined inhibition of JNK and LIMK2 may improve erectile function by suppressing cavernosal apoptosis and fibrosis via restoration of cJun/Bcl-2/Bax and LIMK2/Cofilin pathways at 10 days after CN injury.

AB - Objective: To determine if combined administration of LIMK2 and JNK inhibitors in a rat model of erectile dysfunction induced by cavernosal nerve (CN) injury could restore erectile function by suppressing both cavernosal apoptosis and fibrosis via rectification of molecular pathways related to the structural alterations. Methods: Sixty 12-week-old male Sprague-Dawley rats were categorized into 4 groups: (1) Sham-surgery (Sham) group, (2) CN-crush-injury (CNCI), (3) CNCI group (CNCI+L+1.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and low-dose (1.0 mg/kg) JNK-inhibitors, and (4) CNCI group (CNCI+L+10.0J) treated with a combination of 10.0 mg/kg LIMK2-inhibitors and a high dose (10.0 mg/kg) of JNK-inhibitors. Ten days after surgery, erectile response, histological-studies, and Western-blot was investigated. Results: The CNCI group showed a reduced maximal ICP/MAP or AUC/MAP, decreased immunohistochemical-staining of α-SMA, decreased SM/collagen ratio, increased phospho-cJun-positive apoptotic cells, increased phospho-LIMK2-positive fibroblasts, increased cJun-phosphorylation, increased LIMK2/Cofilin-phosphorylation, decreased Bcl-2/Bax ratio, and increased protein-expression of fibronectin, compared to the Sham group. Both the CNCI+L+1.0J and CNCI+L+10.0J groups showed improvements in erectile-responses, content of cavernosal α-SMA, number of phospho-cJun-positive apoptotic cells, Bcl-2/Bax ratio and cJun phosphorylation. Their improvements in the CNCI+L+10.0J group showed a tendency to be greater than those in the CNCI+L+1.0J group. Also, in the 2 treatment groups, rectification of SM/collagen ratio, number of phospho-LIMK2-positive fibroblasts, LIMK2/Cofilin-phosphorylation, and protein-expression of fibronectin was observed. Conclusion: This study suggests that combined inhibition of JNK and LIMK2 may improve erectile function by suppressing cavernosal apoptosis and fibrosis via restoration of cJun/Bcl-2/Bax and LIMK2/Cofilin pathways at 10 days after CN injury.

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U2 - 10.1016/j.urology.2019.06.005

DO - 10.1016/j.urology.2019.06.005

M3 - Article

VL - 131

SP - 136

EP - 143

JO - Urology

JF - Urology

SN - 0090-4295

ER -