Netrin-1 is a novel regulator of vascular endothelial function in diabetes

Haroldo Alfredo Flores Toque, Aracely Fernandez-Flores, Riyaz Mohamed, Ruth B Caldwell, Ganesan Ramesh, Robert William Caldwell

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Netrin-1, a secreted laminin-like protein identified as an axon guidance molecule, has been shown to be of critical importance in the cardiovascular system. Recent studies have revealed pro-angiogenic, anti-apoptotic and anti-inflammatory properties of netrin-1 as well as cardioprotective actions against myocardial injury in diabetic mice. Aim: To examine the role of netrin-1 in diabetes-and high glucose (HG)-induced vascular endothelial dysfunction (VED) using netrin-1 transgenic mice (Tg3) and cultured bovine aortic endothelial cells (BAEC). Main outcome: Overexpression of netrin-1 prevented diabetes-induced VED in aorta from diabetic mice and netrin-1 treatment attenuated HG-induced impairment of nitric oxide synthase (NOS) function in BAECs. Methods and results: Experiments were performed in Tg3 and littermate control (WT) mice rendered diabetic with streptozotocin (STZ) and in BAECs treated with HG (25 mmol/L). Levels of netrin-1 and its receptor DCC, markers of inflammation and apoptosis and vascular function were assessed in aortas from diabetic and non-diabetic Tg3 and WT mice. Vascular netrin-1 in WT mice was reduced under diabetic conditions. Aortas from non-diabetic Tg3 and WT mice showed similar maximum endothelium-dependent relaxation (MEDR) (83% and 87%, respectively). MEDR was markedly impaired in aorta from diabetic WT mice (51%). This effect was significantly blunted in Tg3 diabetic aortas (70%). Improved vascular relaxation in Tg3 diabetic mice was associated with increased levels of phospho-ERK1/2 and reduced levels of oxidant stress, NFêB, COX-2, p16INK4A, cleaved caspase-3 and p16 and p53 mRNA. Netrin-1 treatment prevented the HG-induced decrease in NO production and elevation of oxidative stress and apoptosis in BAECs. Conclusions: Diabetes decreases aortic levels of netrin-1. However, overexpression of netrin-1 attenuates diabetes-induced VED and limits the reduction of NO levels, while increasing expression of p-ERK1/2, and suppressing oxidative stress and inflammatory and apoptotic processes. Enhancement of netrin-1 function may be a useful therapeutic means for preventing vascular dysfunction in diabetes.

Original languageEnglish (US)
Article numbere0186734
JournalPloS one
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2017

Fingerprint

Medical problems
blood vessels
Blood Vessels
diabetes
aorta
mice
Aorta
glucose
Glucose
endothelium
Oxidative stress
oxidative stress
apoptosis
Endothelium
Oxidative Stress
netrin-1
laminin
cardiovascular system
Apoptosis
streptozotocin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Netrin-1 is a novel regulator of vascular endothelial function in diabetes. / Flores Toque, Haroldo Alfredo; Fernandez-Flores, Aracely; Mohamed, Riyaz; Caldwell, Ruth B; Ramesh, Ganesan; Caldwell, Robert William.

In: PloS one, Vol. 12, No. 10, e0186734, 01.10.2017.

Research output: Contribution to journalArticle

@article{078bd055439c4d0a8ad562d5c7305061,
title = "Netrin-1 is a novel regulator of vascular endothelial function in diabetes",
abstract = "Background: Netrin-1, a secreted laminin-like protein identified as an axon guidance molecule, has been shown to be of critical importance in the cardiovascular system. Recent studies have revealed pro-angiogenic, anti-apoptotic and anti-inflammatory properties of netrin-1 as well as cardioprotective actions against myocardial injury in diabetic mice. Aim: To examine the role of netrin-1 in diabetes-and high glucose (HG)-induced vascular endothelial dysfunction (VED) using netrin-1 transgenic mice (Tg3) and cultured bovine aortic endothelial cells (BAEC). Main outcome: Overexpression of netrin-1 prevented diabetes-induced VED in aorta from diabetic mice and netrin-1 treatment attenuated HG-induced impairment of nitric oxide synthase (NOS) function in BAECs. Methods and results: Experiments were performed in Tg3 and littermate control (WT) mice rendered diabetic with streptozotocin (STZ) and in BAECs treated with HG (25 mmol/L). Levels of netrin-1 and its receptor DCC, markers of inflammation and apoptosis and vascular function were assessed in aortas from diabetic and non-diabetic Tg3 and WT mice. Vascular netrin-1 in WT mice was reduced under diabetic conditions. Aortas from non-diabetic Tg3 and WT mice showed similar maximum endothelium-dependent relaxation (MEDR) (83{\%} and 87{\%}, respectively). MEDR was markedly impaired in aorta from diabetic WT mice (51{\%}). This effect was significantly blunted in Tg3 diabetic aortas (70{\%}). Improved vascular relaxation in Tg3 diabetic mice was associated with increased levels of phospho-ERK1/2 and reduced levels of oxidant stress, NF{\^e}B, COX-2, p16INK4A, cleaved caspase-3 and p16 and p53 mRNA. Netrin-1 treatment prevented the HG-induced decrease in NO production and elevation of oxidative stress and apoptosis in BAECs. Conclusions: Diabetes decreases aortic levels of netrin-1. However, overexpression of netrin-1 attenuates diabetes-induced VED and limits the reduction of NO levels, while increasing expression of p-ERK1/2, and suppressing oxidative stress and inflammatory and apoptotic processes. Enhancement of netrin-1 function may be a useful therapeutic means for preventing vascular dysfunction in diabetes.",
author = "{Flores Toque}, {Haroldo Alfredo} and Aracely Fernandez-Flores and Riyaz Mohamed and Caldwell, {Ruth B} and Ganesan Ramesh and Caldwell, {Robert William}",
year = "2017",
month = "10",
day = "1",
doi = "10.1371/journal.pone.0186734",
language = "English (US)",
volume = "12",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Netrin-1 is a novel regulator of vascular endothelial function in diabetes

AU - Flores Toque, Haroldo Alfredo

AU - Fernandez-Flores, Aracely

AU - Mohamed, Riyaz

AU - Caldwell, Ruth B

AU - Ramesh, Ganesan

AU - Caldwell, Robert William

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Background: Netrin-1, a secreted laminin-like protein identified as an axon guidance molecule, has been shown to be of critical importance in the cardiovascular system. Recent studies have revealed pro-angiogenic, anti-apoptotic and anti-inflammatory properties of netrin-1 as well as cardioprotective actions against myocardial injury in diabetic mice. Aim: To examine the role of netrin-1 in diabetes-and high glucose (HG)-induced vascular endothelial dysfunction (VED) using netrin-1 transgenic mice (Tg3) and cultured bovine aortic endothelial cells (BAEC). Main outcome: Overexpression of netrin-1 prevented diabetes-induced VED in aorta from diabetic mice and netrin-1 treatment attenuated HG-induced impairment of nitric oxide synthase (NOS) function in BAECs. Methods and results: Experiments were performed in Tg3 and littermate control (WT) mice rendered diabetic with streptozotocin (STZ) and in BAECs treated with HG (25 mmol/L). Levels of netrin-1 and its receptor DCC, markers of inflammation and apoptosis and vascular function were assessed in aortas from diabetic and non-diabetic Tg3 and WT mice. Vascular netrin-1 in WT mice was reduced under diabetic conditions. Aortas from non-diabetic Tg3 and WT mice showed similar maximum endothelium-dependent relaxation (MEDR) (83% and 87%, respectively). MEDR was markedly impaired in aorta from diabetic WT mice (51%). This effect was significantly blunted in Tg3 diabetic aortas (70%). Improved vascular relaxation in Tg3 diabetic mice was associated with increased levels of phospho-ERK1/2 and reduced levels of oxidant stress, NFêB, COX-2, p16INK4A, cleaved caspase-3 and p16 and p53 mRNA. Netrin-1 treatment prevented the HG-induced decrease in NO production and elevation of oxidative stress and apoptosis in BAECs. Conclusions: Diabetes decreases aortic levels of netrin-1. However, overexpression of netrin-1 attenuates diabetes-induced VED and limits the reduction of NO levels, while increasing expression of p-ERK1/2, and suppressing oxidative stress and inflammatory and apoptotic processes. Enhancement of netrin-1 function may be a useful therapeutic means for preventing vascular dysfunction in diabetes.

AB - Background: Netrin-1, a secreted laminin-like protein identified as an axon guidance molecule, has been shown to be of critical importance in the cardiovascular system. Recent studies have revealed pro-angiogenic, anti-apoptotic and anti-inflammatory properties of netrin-1 as well as cardioprotective actions against myocardial injury in diabetic mice. Aim: To examine the role of netrin-1 in diabetes-and high glucose (HG)-induced vascular endothelial dysfunction (VED) using netrin-1 transgenic mice (Tg3) and cultured bovine aortic endothelial cells (BAEC). Main outcome: Overexpression of netrin-1 prevented diabetes-induced VED in aorta from diabetic mice and netrin-1 treatment attenuated HG-induced impairment of nitric oxide synthase (NOS) function in BAECs. Methods and results: Experiments were performed in Tg3 and littermate control (WT) mice rendered diabetic with streptozotocin (STZ) and in BAECs treated with HG (25 mmol/L). Levels of netrin-1 and its receptor DCC, markers of inflammation and apoptosis and vascular function were assessed in aortas from diabetic and non-diabetic Tg3 and WT mice. Vascular netrin-1 in WT mice was reduced under diabetic conditions. Aortas from non-diabetic Tg3 and WT mice showed similar maximum endothelium-dependent relaxation (MEDR) (83% and 87%, respectively). MEDR was markedly impaired in aorta from diabetic WT mice (51%). This effect was significantly blunted in Tg3 diabetic aortas (70%). Improved vascular relaxation in Tg3 diabetic mice was associated with increased levels of phospho-ERK1/2 and reduced levels of oxidant stress, NFêB, COX-2, p16INK4A, cleaved caspase-3 and p16 and p53 mRNA. Netrin-1 treatment prevented the HG-induced decrease in NO production and elevation of oxidative stress and apoptosis in BAECs. Conclusions: Diabetes decreases aortic levels of netrin-1. However, overexpression of netrin-1 attenuates diabetes-induced VED and limits the reduction of NO levels, while increasing expression of p-ERK1/2, and suppressing oxidative stress and inflammatory and apoptotic processes. Enhancement of netrin-1 function may be a useful therapeutic means for preventing vascular dysfunction in diabetes.

UR - http://www.scopus.com/inward/record.url?scp=85032215552&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032215552&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0186734

DO - 10.1371/journal.pone.0186734

M3 - Article

C2 - 29059224

AN - SCOPUS:85032215552

VL - 12

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e0186734

ER -