Inhibition of Jun N-terminal Kinase Improves Erectile Function by Alleviation of Cavernosal Apoptosis in a Rat Model of Cavernous Nerve Injury

Park, Juhyun; Chai, Ji Sun; Kim, Soowoong; Paick, Jae Seung; Cho, Min Chul

doi:10.1016/j.urology.2017.11.040

Cited by 15 publications

(39 citation statements)

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“…Activation of JNK and p38 MAPK signaling pathway can promote the apoptosis in the early stage of the corpus cavernosum injury. 12,13 Furthermore, p38 MAPK signaling pathway can induce vascular smooth muscle cell (VSMC) phenotypic transformation. 14e16 However, the effect of the MAPK pathway on phenotypic transformation of CCSMCs after CN injury is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Induced Phenotypic Transformation of Corpus Cavernosum Smooth Muscle Cells After Cavernous Nerve Crush Injury by Down-Regulating P38 Mitogen-Activated Protein Kinase Expression

et al. 2019

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Introduction: Cavernosal nerve (CN) injury is commonly caused by radical prostatectomy surgery, and it might directly lead to erectile dysfunction (ED). Currently, the role of mitogen-activated protein kinase (MAPK) family proteins in phenotypic transformation of corpus cavernosum smooth muscle cell (CCSMC) after CNs injury is poorly understood. Aim: To investigate the role of p38 MAPK in hypoxia-induced phenotypic transformation of CCSMCs after CN injury. Methods: In total, 20 SpragueeDawley rats (male and 8 weeks of age) were randomly divided into 2 groups, including a sham group and CNCI group. In the sham group, rats were sham-operated by identifying 2 CNs without causing direct damage to the CNs. In the CNCI group, rats were subjected to bilateral CN crush injury. CCSMCs were isolated from the normal corpus cavernosum tissues of the SpragueeDawley rat and then cultured in 21% or 1% O 2 concentration context for 48 hours. Main Outcome Measures: Intracavernous pressure/mean arterial pressure were analyzed to measure erectile response. The impact of hypoxia on penile pathology, as well as the expression of extracellular signal-regulated kinases, the c-Jun NH2-terminal kinase, and p38 MAPK, were analyzed. Results: Compared with the sham group, the intracavernous pressure/mean arterial pressure rate and a-smooth muscle actin expression of CNCI group were decreased significantly (P ¼ .0001; P ¼ .016, respectively), but vimentin expression was significantly increased (P ¼ .023). Phosphorylated p38 level in CNCI group was decreased significantly (P ¼ .017; sham: 0.17 ± 0.005; CNCI: 0.14 ± 0.02). The CCSMCs in the normoxia group were long fusiform, whereas the morphology of CCSMCs in the hypoxia group became hypertrophic. After hypoxia for 48 hours, the expression of a-smooth muscle actin and phosphorylated p38 MAPK was decreased significantly (P ¼ .01; P ¼ .024, normoxia: 0.66 ± 0.18, hypoxia: 0.26 ± 0.08, respectively), and the expression of hypoxia-inducible factor-1a and collagen I was increased significantly in hypoxia group (P ¼ .04; P ¼ .012, respectively). Conclusions: Hypoxia induced the phenotypic transformation of CCSMCs after CNCI might be associated with the downregulation of phosphorylated p38 MAPK. Chen S, Huang X, Kong X, et al. Hypoxia-Induced

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Section: Introductionmentioning

confidence: 99%

Hypoxia-Induced Phenotypic Transformation of Corpus Cavernosum Smooth Muscle Cells After Cavernous Nerve Crush Injury by Down-Regulating P38 Mitogen-Activated Protein Kinase Expression

et al. 2019

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“…Erectile function was determined using a standardized model by electrical stimulation of the CNs at 2 weeks after surgery to generate erectile responses as described previously 10202122. After a lower midline incision, major pelvic ganglions and the CNs were isolated.…”

Section: Methodsmentioning

confidence: 99%

“…For each stained slide, areas of SM (stained in red) and collagen fibril (stained in blue) were analyzed. To determine SM content in the cavernous tissue, immunohistochemical staining was carried out using a primary antibody against α-SM actin (α-SMA) (1:100, Dako, Glostrup, Denmark) as described previously 101920…”

Section: Methodsmentioning

confidence: 99%

“…As described previously,1019202122 western blot assay was carried out to determine protein expression levels. Briefly, after cavernous tissue samples were homogenized, equal amounts of protein (50 μg in each well) were electrophoresed on Mini Protean TGX gels (7.5% or 12.0%; Bio-Rad, Hercules, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Thus, cavernous apoptosis and fibrosis are important contributors to post-RP ED. A few potential therapies for cavernous apoptosis including phosphodiesterase type 5 inhibitors (PDE5is), Rho-kinase inhibitors, intracavernous delivery of sonic hedgehog, intracavernous stem cell injection, and Jun amino-terminal kinase (JNK) inhibitors have been tested in rat models of ED induced by CN injury 578910. Although these studies have shown positive results in terms of improving cavernous apoptosis or ED,578910 their routine use is limited due to insufficient clinical efficacy of PDE5is, potential adverse effects of Rho kinase inhibitors, pending safety issues of stem cell therapy, and insufficient data on sonic hedgehog or JNK inhibitors 11121314…”

Section: Introductionmentioning

confidence: 99%

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The effects of single versus combined therapy using LIM-kinase 2 inhibitor and type 5 phosphodiesterase inhibitor on erectile function in a rat model of cavernous nerve injury-induced erectile dysfunction

et al. 2019

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We aimed to determine whether combination of LIM-kinase 2 inhibitor (LIMK2i) and phosphodiesterase type-5 inhibitor (PDE5i) could restore erectile function through suppressing cavernous fibrosis and improving cavernous apoptosis in a rat model of cavernous nerve crush injury (CNCI). Seventy 12-week-old Sprague–Dawley rats were equally distributed into five groups as follows: (1) sham surgery (Group S), (2) CNCI (Group I), (3) CNCI treated with daily intraperitoneal administration of 10.0 mg kg −1 LIMK2i (Group I + L), (4) daily oral administration of 20.0 mg kg −1 udenafil, PDE5i (Group I + U), and (5) combined administration of 10.0 mg kg −1 LIMK2i and 20.0 mg kg −1 udenafil (Group I + L + U). Rats in Groups I + L, I + U, and I + L + U were treated with respective regimens for 2 weeks after CNCI. At 2 weeks after surgery, erectile response was assessed using electrostimulation. Penile tissues were processed for histological studies and western blot. Group I showed lower intracavernous pressure (ICP)/mean arterial pressure (MAP), lower area under the curve (AUC)/MAP, decreased immunohistochemical staining for alpha-smooth muscle (SM) actin, higher apoptotic index, lower SM/collagen ratio, increased phospho-LIMK2-positive fibroblasts, decreased protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) phosphorylation, increased LIMK2/cofilin phosphorylation, and increased protein expression of fibronectin, compared to Group S. In all three treatment groups, erectile responses, protein expression of fibronectin, and SM/collagen ratio were improved. Group I + L + U showed greater improvement in erectile response than Group I + L. SM content and apoptotic index in Groups I + U and I + L + U were improved compared to those in Group I. However, Group I + L did not show a significant improvement in SM content or apoptotic index. The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I + L and I + L + U, but not in Group I + U. Akt/eNOS phosphorylation was improved in Groups I + U and I + L + U, but not in Group I + L. LIMK2/cofilin phosphorylation was improved in Groups I + L and I + L + U, but not in Group I + U. Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis. Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.

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Restoration of erectile function by a combination of antiapoptosis by JNK inhibitor and preservation of smooth muscle or endothelium by hepatocyte growth factor in a rat model of cavernous nerve injury

Kim

Lee

et al. 2021

The Prostate

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Background: Because of structural alterations in the corpus cavernosum after radical prostatectomy (RP), post-RP erectile dysfunction remains a very difficult condition to treat. We aimed to determine if the combined administration of a Jun-amino terminal kinase (JNK) inhibitor and hepatocyte growth factor (HGF) in the immediate post-injury period would restore erectile function by antiapoptotic and proregenerative effects through the rectification of molecular pathways related to the structural integrity of the penis in a rat model of bilateral cavernosal nerve crush injury (CNCI).Methods: A total of 70 rats were divided into five groups: Sham surgery (S), CNCI (I), and once-daily intraperitoneal administration of 10.0 mg/kg JNK inhibitor + twiceweekly intracavernosal administration of low-dose (2.1 μg), medium-dose (4.2 μg), or high-dose (8.4 μg) HGF (I + J + LH or I + J + MH or I + J + HH, respectively) in the immediate post-injury period. Erectile responses to electrostimulation (1.0, 3.0, and 5.0 V), histological staining, caspase-3 activity, and Western blotting were evaluated 9 days after surgery.Results: Group I showed lower intracavernosal pressure (ICP)/mean arterial pressure (MAP) after stimulation at each voltage, lower area under the curve (AUC)/MAP after stimulation at each voltage, less smooth muscle (SM) content, a lower SM/ collagen ratio, higher caspase-3 activity, increased cJun phosphorylation, decreased protein expression of PECAM-1, decreased cMet phosphorylation, and decreased endothelial nitric oxide synthase (eNOS) phosphorylation compared to Group S. The SM content, SM/collagen ratio, protein expression of ICP/MAP, or AUC/MAP after stimulation at each voltage in Group I + J + LH were partially restored, despite the normalization of cJun phosphorylation and caspase-3 activity. The ICP/MAP, AUC/MAP, caspase-3 activity, SM content, protein expression of PECAM-1, cJun phosphorylation, cMet phosphorylation, and eNOS phosphorylation in both Groups I + J + MH and I + J + HH were restored to the levels observed in Group S, while the SM/collagen ratio was significantly improved but not completely normalized.

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Inhibition of Jun N-terminal Kinase Improves Erectile Function by Alleviation of Cavernosal Apoptosis in a Rat Model of Cavernous Nerve Injury

Cited by 15 publications

References 18 publications

Hypoxia-Induced Phenotypic Transformation of Corpus Cavernosum Smooth Muscle Cells After Cavernous Nerve Crush Injury by Down-Regulating P38 Mitogen-Activated Protein Kinase Expression

Hypoxia-Induced Phenotypic Transformation of Corpus Cavernosum Smooth Muscle Cells After Cavernous Nerve Crush Injury by Down-Regulating P38 Mitogen-Activated Protein Kinase Expression

The effects of single versus combined therapy using LIM-kinase 2 inhibitor and type 5 phosphodiesterase inhibitor on erectile function in a rat model of cavernous nerve injury-induced erectile dysfunction

Restoration of erectile function by a combination of antiapoptosis by JNK inhibitor and preservation of smooth muscle or endothelium by hepatocyte growth factor in a rat model of cavernous nerve injury

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