Endothelial dysfunction in the streptozotocin-induced diabetic apoE-deficient mouse

Hong Ding; Michael Hashem; William B Wiehler; Winnie Lau; Jackie Martin; Julianne Reid; Chris Triggle

doi:10.1038/sj.bjp.0706417

Endothelial dysfunction in the streptozotocin-induced diabetic apoE-deficient mouse

Hong Ding, Michael Hashem, William B Wiehler, Winnie Lau, Jackie Martin, Julianne Reid, Chris Triggle

Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Endothelial dysfunction plays a role in the development of atherosclerosis and diabetes-associated vascular disease and, in the streptozotocin (STZ)-induced apoE-deficient diabetic mouse, we report that, when compared to the citrate (CIT)-treated nondiabetic apoE-deficient control, acetylcholine (Ach)-mediated endothelium-dependent relaxation was reduced in the small mesenteric arteries (SMA) and the plaque-prone regions of the aorta from the STZ-diabetic mouse. In the SMA the component of Ach-mediated relaxation that was attributed to nitric oxide (NO) from STZ-treated diabetic apoE-deficient mice was enhanced; however, the endothelium-derived hyperpolarizing factor (EDHF)-mediated component was reduced. The EDHF component was assessed by determining the component of the Ach-mediated response that was resistant to the combination of the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester, cyclooxygenase inhibitor, indomethacin, and soluble guanylate cyclase inhibitor, ODQ, and inhibited by the combination of the intermediate conductance KCa (IKCa) inhibitor TRAM-34 and the small-conductance KCa (SKCa) inhibitor apamin. Endothelial NOS was increased but SK2, SK3 and connexin (Cx) 37 mRNA expressions were significantly (P<0.05) decreased in the SMA from STZ-treated apoE-deficient mice compared to the CIT-treated controls. There was no difference in the IKCa expression or in Cx 40, 43 and 45 mRNA levels between STZ- and CIT-treated mice. The microvasculature of STZ-induced apoE-deficient mice developed endothelial dysfunction, which may be linked to a decrease in the contribution of the EDHF component due to a decrease in SK2 and 3 and Cx 37 expression.

Original language	English
Pages (from-to)	1110-8
Number of pages	9
Journal	BRITISH JOURNAL OF PHARMACOLOGY
Volume	146
Issue number	8
DOIs	https://doi.org/10.1038/sj.bjp.0706417
Publication status	Published - Dec 2005

Keywords

Acetylcholine
Animals
Aorta
Apolipoproteins E
Biological Factors
Connexins
Diabetes Mellitus, Experimental
Dose-Response Relationship, Drug
Endothelium, Vascular
Mesenteric Arteries
Mice
Mice, Knockout
Nitric Oxide
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
RNA, Messenger
Small-Conductance Calcium-Activated Potassium Channels
Streptozocin
Vasodilation
Vasodilator Agents

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10.1038/sj.bjp.0706417

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title = "Endothelial dysfunction in the streptozotocin-induced diabetic apoE-deficient mouse",

abstract = "Endothelial dysfunction plays a role in the development of atherosclerosis and diabetes-associated vascular disease and, in the streptozotocin (STZ)-induced apoE-deficient diabetic mouse, we report that, when compared to the citrate (CIT)-treated nondiabetic apoE-deficient control, acetylcholine (Ach)-mediated endothelium-dependent relaxation was reduced in the small mesenteric arteries (SMA) and the plaque-prone regions of the aorta from the STZ-diabetic mouse. In the SMA the component of Ach-mediated relaxation that was attributed to nitric oxide (NO) from STZ-treated diabetic apoE-deficient mice was enhanced; however, the endothelium-derived hyperpolarizing factor (EDHF)-mediated component was reduced. The EDHF component was assessed by determining the component of the Ach-mediated response that was resistant to the combination of the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester, cyclooxygenase inhibitor, indomethacin, and soluble guanylate cyclase inhibitor, ODQ, and inhibited by the combination of the intermediate conductance KCa (IKCa) inhibitor TRAM-34 and the small-conductance KCa (SKCa) inhibitor apamin. Endothelial NOS was increased but SK2, SK3 and connexin (Cx) 37 mRNA expressions were significantly (P<0.05) decreased in the SMA from STZ-treated apoE-deficient mice compared to the CIT-treated controls. There was no difference in the IKCa expression or in Cx 40, 43 and 45 mRNA levels between STZ- and CIT-treated mice. The microvasculature of STZ-induced apoE-deficient mice developed endothelial dysfunction, which may be linked to a decrease in the contribution of the EDHF component due to a decrease in SK2 and 3 and Cx 37 expression.",

keywords = "Acetylcholine, Animals, Aorta, Apolipoproteins E, Biological Factors, Connexins, Diabetes Mellitus, Experimental, Dose-Response Relationship, Drug, Endothelium, Vascular, Mesenteric Arteries, Mice, Mice, Knockout, Nitric Oxide, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, RNA, Messenger, Small-Conductance Calcium-Activated Potassium Channels, Streptozocin, Vasodilation, Vasodilator Agents",

author = "Hong Ding and Michael Hashem and Wiehler, {William B} and Winnie Lau and Jackie Martin and Julianne Reid and Chris Triggle",

year = "2005",

month = dec,

doi = "10.1038/sj.bjp.0706417",

language = "English",

volume = "146",

pages = "1110--8",

journal = "BRITISH JOURNAL OF PHARMACOLOGY",

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T1 - Endothelial dysfunction in the streptozotocin-induced diabetic apoE-deficient mouse

AU - Ding, Hong

AU - Hashem, Michael

AU - Wiehler, William B

AU - Lau, Winnie

AU - Martin, Jackie

AU - Reid, Julianne

AU - Triggle, Chris

PY - 2005/12

Y1 - 2005/12

N2 - Endothelial dysfunction plays a role in the development of atherosclerosis and diabetes-associated vascular disease and, in the streptozotocin (STZ)-induced apoE-deficient diabetic mouse, we report that, when compared to the citrate (CIT)-treated nondiabetic apoE-deficient control, acetylcholine (Ach)-mediated endothelium-dependent relaxation was reduced in the small mesenteric arteries (SMA) and the plaque-prone regions of the aorta from the STZ-diabetic mouse. In the SMA the component of Ach-mediated relaxation that was attributed to nitric oxide (NO) from STZ-treated diabetic apoE-deficient mice was enhanced; however, the endothelium-derived hyperpolarizing factor (EDHF)-mediated component was reduced. The EDHF component was assessed by determining the component of the Ach-mediated response that was resistant to the combination of the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester, cyclooxygenase inhibitor, indomethacin, and soluble guanylate cyclase inhibitor, ODQ, and inhibited by the combination of the intermediate conductance KCa (IKCa) inhibitor TRAM-34 and the small-conductance KCa (SKCa) inhibitor apamin. Endothelial NOS was increased but SK2, SK3 and connexin (Cx) 37 mRNA expressions were significantly (P<0.05) decreased in the SMA from STZ-treated apoE-deficient mice compared to the CIT-treated controls. There was no difference in the IKCa expression or in Cx 40, 43 and 45 mRNA levels between STZ- and CIT-treated mice. The microvasculature of STZ-induced apoE-deficient mice developed endothelial dysfunction, which may be linked to a decrease in the contribution of the EDHF component due to a decrease in SK2 and 3 and Cx 37 expression.

AB - Endothelial dysfunction plays a role in the development of atherosclerosis and diabetes-associated vascular disease and, in the streptozotocin (STZ)-induced apoE-deficient diabetic mouse, we report that, when compared to the citrate (CIT)-treated nondiabetic apoE-deficient control, acetylcholine (Ach)-mediated endothelium-dependent relaxation was reduced in the small mesenteric arteries (SMA) and the plaque-prone regions of the aorta from the STZ-diabetic mouse. In the SMA the component of Ach-mediated relaxation that was attributed to nitric oxide (NO) from STZ-treated diabetic apoE-deficient mice was enhanced; however, the endothelium-derived hyperpolarizing factor (EDHF)-mediated component was reduced. The EDHF component was assessed by determining the component of the Ach-mediated response that was resistant to the combination of the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester, cyclooxygenase inhibitor, indomethacin, and soluble guanylate cyclase inhibitor, ODQ, and inhibited by the combination of the intermediate conductance KCa (IKCa) inhibitor TRAM-34 and the small-conductance KCa (SKCa) inhibitor apamin. Endothelial NOS was increased but SK2, SK3 and connexin (Cx) 37 mRNA expressions were significantly (P<0.05) decreased in the SMA from STZ-treated apoE-deficient mice compared to the CIT-treated controls. There was no difference in the IKCa expression or in Cx 40, 43 and 45 mRNA levels between STZ- and CIT-treated mice. The microvasculature of STZ-induced apoE-deficient mice developed endothelial dysfunction, which may be linked to a decrease in the contribution of the EDHF component due to a decrease in SK2 and 3 and Cx 37 expression.

KW - Acetylcholine

KW - Animals

KW - Aorta

KW - Apolipoproteins E

KW - Biological Factors

KW - Connexins

KW - Diabetes Mellitus, Experimental

KW - Dose-Response Relationship, Drug

KW - Endothelium, Vascular

KW - Mesenteric Arteries

KW - Mice

KW - Mice, Knockout

KW - Nitric Oxide

KW - Nitric Oxide Synthase Type II

KW - Nitric Oxide Synthase Type III

KW - RNA, Messenger

KW - Small-Conductance Calcium-Activated Potassium Channels

KW - Streptozocin

KW - Vasodilation

KW - Vasodilator Agents

U2 - 10.1038/sj.bjp.0706417

DO - 10.1038/sj.bjp.0706417

M3 - Article

C2 - 16231005

SN - 0007-1188

VL - 146

SP - 1110

EP - 1118

JO - BRITISH JOURNAL OF PHARMACOLOGY

JF - BRITISH JOURNAL OF PHARMACOLOGY

IS - 8

ER -