Extracellular Signal-Regulated Kinase (ERK) Inhibition Decreases Arginase Activity and Improves Corpora Cavernosal Relaxation in Streptozotocin (STZ)-Induced Diabetic Mice

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Abstract

Introduction. Increased arginase activity (AA) has been implicated in hypertension and diabetes-induced endothelial dysfunction by reducing L-arginine availability and nitric oxide production. Higher levels of active extracellular signal-regulated kinase (ERK) have been found in patients with erectile dysfunction (ED) compared to patients without it. Both ERK and arginase have been reported to affect the expression and activity of nitric oxide synthase (NOS) and consequently penile erection. Nevertheless, signaling pathways activated by ERK in the penis are not well known. Aim. We hypothesized that inhibition of ERK by ERK inhibitor PD98059 decreases AA and thus improves cavernosal relaxation in streptozotocin (STZ)-diabetic mice. Methods. The AA, ERK, eNOS, and arginase I and II expressions were examined through Western blot, and functional response of cavernosal tissue were determined. Control and diabetic cavernosal tissues were pretreated with PD98059 (10-5M) and arginase inhibitor ((S)-(2-boronoethyl)-L-cysteine hydrochloride, [BEC]10-4M]). Main Outcome Measures. Diabetes increased AA significantly (twofold) over control mice and this effect was blocked by acute treatment with PD98059. Cavernosal strips from diabetic mice exhibited decreased relaxation (STZ-diabetic vs. control, respectively) to both the endothelium-dependent agonist acetylcholine (38.0±5% vs. 82.5±7%) and nitrergic stimulation (27±2% vs. 76±6%) by electrical field stimulation (EFS, 1-32Hz). However, this impairment in cavernosal relaxation from diabetic mice was attenuated by treatment with PD98059 in nitrergic (27±2% vs. 60±4%) and endothelium-dependent relaxation responses (38.0±5% vs. 67.5±6%). Acute treatment with the arginase inhibitor BEC (10-4M) also improves EFS-induced relaxation in diabetic mice (31±3% vs. 49±2%). Moreover, vascular expression of activated ERK was increased in diabetic over control mice. Conclusion. These data suggest that ERK inhibition prevents elevation of penile AA and protects against ED caused by diabetes.

Original languageEnglish (US)
Pages (from-to)3335-3344
Number of pages10
JournalJournal of Sexual Medicine
Volume8
Issue number12
DOIs
StatePublished - Jan 1 2011

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Arginase
Extracellular Signal-Regulated MAP Kinases
Streptozocin
Erectile Dysfunction
Endothelium
Penile Erection
Inhibition (Psychology)
Cholinergic Agonists
Penis
Nitric Oxide Synthase
Electric Stimulation
Cysteine
Blood Vessels
Arginine
Nitric Oxide
Therapeutics
Western Blotting
Outcome Assessment (Health Care)
Hypertension
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Keywords

  • Arginase activity
  • Diabetes
  • ERK
  • Erectile dysfunction
  • Nitric oxide

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology
  • Urology

Cite this

@article{29ec077791c84b2f9797d227db4d8002,
title = "Extracellular Signal-Regulated Kinase (ERK) Inhibition Decreases Arginase Activity and Improves Corpora Cavernosal Relaxation in Streptozotocin (STZ)-Induced Diabetic Mice",
abstract = "Introduction. Increased arginase activity (AA) has been implicated in hypertension and diabetes-induced endothelial dysfunction by reducing L-arginine availability and nitric oxide production. Higher levels of active extracellular signal-regulated kinase (ERK) have been found in patients with erectile dysfunction (ED) compared to patients without it. Both ERK and arginase have been reported to affect the expression and activity of nitric oxide synthase (NOS) and consequently penile erection. Nevertheless, signaling pathways activated by ERK in the penis are not well known. Aim. We hypothesized that inhibition of ERK by ERK inhibitor PD98059 decreases AA and thus improves cavernosal relaxation in streptozotocin (STZ)-diabetic mice. Methods. The AA, ERK, eNOS, and arginase I and II expressions were examined through Western blot, and functional response of cavernosal tissue were determined. Control and diabetic cavernosal tissues were pretreated with PD98059 (10-5M) and arginase inhibitor ((S)-(2-boronoethyl)-L-cysteine hydrochloride, [BEC]10-4M]). Main Outcome Measures. Diabetes increased AA significantly (twofold) over control mice and this effect was blocked by acute treatment with PD98059. Cavernosal strips from diabetic mice exhibited decreased relaxation (STZ-diabetic vs. control, respectively) to both the endothelium-dependent agonist acetylcholine (38.0±5{\%} vs. 82.5±7{\%}) and nitrergic stimulation (27±2{\%} vs. 76±6{\%}) by electrical field stimulation (EFS, 1-32Hz). However, this impairment in cavernosal relaxation from diabetic mice was attenuated by treatment with PD98059 in nitrergic (27±2{\%} vs. 60±4{\%}) and endothelium-dependent relaxation responses (38.0±5{\%} vs. 67.5±6{\%}). Acute treatment with the arginase inhibitor BEC (10-4M) also improves EFS-induced relaxation in diabetic mice (31±3{\%} vs. 49±2{\%}). Moreover, vascular expression of activated ERK was increased in diabetic over control mice. Conclusion. These data suggest that ERK inhibition prevents elevation of penile AA and protects against ED caused by diabetes.",
keywords = "Arginase activity, Diabetes, ERK, Erectile dysfunction, Nitric oxide",
author = "Nunes, {Kenia P.} and {Flores Toque}, {Haroldo Alfredo} and Caldwell, {Ruth B} and Caldwell, {Robert William} and Webb, {R Clinton}",
year = "2011",
month = "1",
day = "1",
doi = "10.1111/j.1743-6109.2011.02499.x",
language = "English (US)",
volume = "8",
pages = "3335--3344",
journal = "Journal of Sexual Medicine",
issn = "1743-6095",
publisher = "Wiley-Blackwell",
number = "12",

}

TY - JOUR

T1 - Extracellular Signal-Regulated Kinase (ERK) Inhibition Decreases Arginase Activity and Improves Corpora Cavernosal Relaxation in Streptozotocin (STZ)-Induced Diabetic Mice

AU - Nunes, Kenia P.

AU - Flores Toque, Haroldo Alfredo

AU - Caldwell, Ruth B

AU - Caldwell, Robert William

AU - Webb, R Clinton

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Introduction. Increased arginase activity (AA) has been implicated in hypertension and diabetes-induced endothelial dysfunction by reducing L-arginine availability and nitric oxide production. Higher levels of active extracellular signal-regulated kinase (ERK) have been found in patients with erectile dysfunction (ED) compared to patients without it. Both ERK and arginase have been reported to affect the expression and activity of nitric oxide synthase (NOS) and consequently penile erection. Nevertheless, signaling pathways activated by ERK in the penis are not well known. Aim. We hypothesized that inhibition of ERK by ERK inhibitor PD98059 decreases AA and thus improves cavernosal relaxation in streptozotocin (STZ)-diabetic mice. Methods. The AA, ERK, eNOS, and arginase I and II expressions were examined through Western blot, and functional response of cavernosal tissue were determined. Control and diabetic cavernosal tissues were pretreated with PD98059 (10-5M) and arginase inhibitor ((S)-(2-boronoethyl)-L-cysteine hydrochloride, [BEC]10-4M]). Main Outcome Measures. Diabetes increased AA significantly (twofold) over control mice and this effect was blocked by acute treatment with PD98059. Cavernosal strips from diabetic mice exhibited decreased relaxation (STZ-diabetic vs. control, respectively) to both the endothelium-dependent agonist acetylcholine (38.0±5% vs. 82.5±7%) and nitrergic stimulation (27±2% vs. 76±6%) by electrical field stimulation (EFS, 1-32Hz). However, this impairment in cavernosal relaxation from diabetic mice was attenuated by treatment with PD98059 in nitrergic (27±2% vs. 60±4%) and endothelium-dependent relaxation responses (38.0±5% vs. 67.5±6%). Acute treatment with the arginase inhibitor BEC (10-4M) also improves EFS-induced relaxation in diabetic mice (31±3% vs. 49±2%). Moreover, vascular expression of activated ERK was increased in diabetic over control mice. Conclusion. These data suggest that ERK inhibition prevents elevation of penile AA and protects against ED caused by diabetes.

AB - Introduction. Increased arginase activity (AA) has been implicated in hypertension and diabetes-induced endothelial dysfunction by reducing L-arginine availability and nitric oxide production. Higher levels of active extracellular signal-regulated kinase (ERK) have been found in patients with erectile dysfunction (ED) compared to patients without it. Both ERK and arginase have been reported to affect the expression and activity of nitric oxide synthase (NOS) and consequently penile erection. Nevertheless, signaling pathways activated by ERK in the penis are not well known. Aim. We hypothesized that inhibition of ERK by ERK inhibitor PD98059 decreases AA and thus improves cavernosal relaxation in streptozotocin (STZ)-diabetic mice. Methods. The AA, ERK, eNOS, and arginase I and II expressions were examined through Western blot, and functional response of cavernosal tissue were determined. Control and diabetic cavernosal tissues were pretreated with PD98059 (10-5M) and arginase inhibitor ((S)-(2-boronoethyl)-L-cysteine hydrochloride, [BEC]10-4M]). Main Outcome Measures. Diabetes increased AA significantly (twofold) over control mice and this effect was blocked by acute treatment with PD98059. Cavernosal strips from diabetic mice exhibited decreased relaxation (STZ-diabetic vs. control, respectively) to both the endothelium-dependent agonist acetylcholine (38.0±5% vs. 82.5±7%) and nitrergic stimulation (27±2% vs. 76±6%) by electrical field stimulation (EFS, 1-32Hz). However, this impairment in cavernosal relaxation from diabetic mice was attenuated by treatment with PD98059 in nitrergic (27±2% vs. 60±4%) and endothelium-dependent relaxation responses (38.0±5% vs. 67.5±6%). Acute treatment with the arginase inhibitor BEC (10-4M) also improves EFS-induced relaxation in diabetic mice (31±3% vs. 49±2%). Moreover, vascular expression of activated ERK was increased in diabetic over control mice. Conclusion. These data suggest that ERK inhibition prevents elevation of penile AA and protects against ED caused by diabetes.

KW - Arginase activity

KW - Diabetes

KW - ERK

KW - Erectile dysfunction

KW - Nitric oxide

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U2 - 10.1111/j.1743-6109.2011.02499.x

DO - 10.1111/j.1743-6109.2011.02499.x

M3 - Article

VL - 8

SP - 3335

EP - 3344

JO - Journal of Sexual Medicine

JF - Journal of Sexual Medicine

SN - 1743-6095

IS - 12

ER -