Changes in IP3 Receptor Expression and Function in Aortic Smooth Muscle of Atherosclerotic Mice

Marie Ann Ewart, Azizah Ugusman, Anisha Vishwanath, Tarek A M Almabrouk, Husam Alganga, Omar J. Katwan, Pavlina Hubanova, Susan Currie, Simon Kennedy

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Peroxynitrite is an endothelium-independent vasodilator that induces relaxation via membrane hyperpolarization. The activation of IP3 receptors triggers the opening of potassium channels and hyperpolarization. Previously we found that relaxation to peroxynitrite was maintained during the development of atherosclerosis due to changes in the expression of calcium-regulatory proteins. In this study we investigated: (1) the mechanism of peroxynitrite-induced relaxation in the mouse aorta, (2) the effect of atherosclerosis on relaxation to peroxynitrite and other vasodilators, and (3) the effect of atherosclerosis on the expression and function of the IP3 receptor. Aortic function was studied using wire myography, and atherosclerosis was induced by fat-feeding ApoE-/- mice. The expression of IP3 receptors was studied using Western blotting and immunohistochemistry. Relaxation to peroxynitrite was attenuated by the IP3 antagonists 2-APB and xestospongin C and also the Kv channel blocker 4-aminopyridine (4-AP). Atherosclerosis attenuated vasodilation to cromakalim and the AMPK activator A769662 but not peroxynitrite. Relaxation was attenuated to a greater extent by 2-APB in atherosclerotic aortae despite the reduced expression of IP3 receptors. 4-AP was less effective in ApoE-/- mice fat-fed for 4 months. Peroxynitrite relaxation involves an IP3-induced calcium release and KV channel activation. This mechanism becomes less important as atherosclerosis develops, and relaxation to peroxynitrite may be maintained by increased calcium extrusion.

Original languageEnglish
Pages (from-to)68-78
Number of pages11
JournalJournal of Vascular Research
DOIs
Publication statusAccepted/In press - 1 Apr 2017

Fingerprint

Inositol 1,4,5-Trisphosphate Receptors
Peroxynitrous Acid
Smooth Muscle
Atherosclerosis
4-Aminopyridine
Apolipoproteins E
Calcium
Vasodilator Agents
A 769662
Aorta
Myography
Fats
Cromakalim
AMP-Activated Protein Kinases
Potassium Channels
Vasodilation
Endothelium
Western Blotting
Immunohistochemistry
Membranes

Keywords

  • Aorta
  • Atherosclerosis
  • IP3 receptor
  • Peroxynitrite
  • Potassium channel

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Ewart, M. A., Ugusman, A., Vishwanath, A., Almabrouk, T. A. M., Alganga, H., Katwan, O. J., ... Kennedy, S. (Accepted/In press). Changes in IP3 Receptor Expression and Function in Aortic Smooth Muscle of Atherosclerotic Mice. Journal of Vascular Research, 68-78. https://doi.org/10.1159/000461581

Changes in IP3 Receptor Expression and Function in Aortic Smooth Muscle of Atherosclerotic Mice. / Ewart, Marie Ann; Ugusman, Azizah; Vishwanath, Anisha; Almabrouk, Tarek A M; Alganga, Husam; Katwan, Omar J.; Hubanova, Pavlina; Currie, Susan; Kennedy, Simon.

In: Journal of Vascular Research, 01.04.2017, p. 68-78.

Research output: Contribution to journalArticle

Ewart, MA, Ugusman, A, Vishwanath, A, Almabrouk, TAM, Alganga, H, Katwan, OJ, Hubanova, P, Currie, S & Kennedy, S 2017, 'Changes in IP3 Receptor Expression and Function in Aortic Smooth Muscle of Atherosclerotic Mice', Journal of Vascular Research, pp. 68-78. https://doi.org/10.1159/000461581
Ewart, Marie Ann ; Ugusman, Azizah ; Vishwanath, Anisha ; Almabrouk, Tarek A M ; Alganga, Husam ; Katwan, Omar J. ; Hubanova, Pavlina ; Currie, Susan ; Kennedy, Simon. / Changes in IP3 Receptor Expression and Function in Aortic Smooth Muscle of Atherosclerotic Mice. In: Journal of Vascular Research. 2017 ; pp. 68-78.
@article{9ef2dec5561646d0943a86be3eb5c17f,
title = "Changes in IP3 Receptor Expression and Function in Aortic Smooth Muscle of Atherosclerotic Mice",
abstract = "Peroxynitrite is an endothelium-independent vasodilator that induces relaxation via membrane hyperpolarization. The activation of IP3 receptors triggers the opening of potassium channels and hyperpolarization. Previously we found that relaxation to peroxynitrite was maintained during the development of atherosclerosis due to changes in the expression of calcium-regulatory proteins. In this study we investigated: (1) the mechanism of peroxynitrite-induced relaxation in the mouse aorta, (2) the effect of atherosclerosis on relaxation to peroxynitrite and other vasodilators, and (3) the effect of atherosclerosis on the expression and function of the IP3 receptor. Aortic function was studied using wire myography, and atherosclerosis was induced by fat-feeding ApoE-/- mice. The expression of IP3 receptors was studied using Western blotting and immunohistochemistry. Relaxation to peroxynitrite was attenuated by the IP3 antagonists 2-APB and xestospongin C and also the Kv channel blocker 4-aminopyridine (4-AP). Atherosclerosis attenuated vasodilation to cromakalim and the AMPK activator A769662 but not peroxynitrite. Relaxation was attenuated to a greater extent by 2-APB in atherosclerotic aortae despite the reduced expression of IP3 receptors. 4-AP was less effective in ApoE-/- mice fat-fed for 4 months. Peroxynitrite relaxation involves an IP3-induced calcium release and KV channel activation. This mechanism becomes less important as atherosclerosis develops, and relaxation to peroxynitrite may be maintained by increased calcium extrusion.",
keywords = "Aorta, Atherosclerosis, IP3 receptor, Peroxynitrite, Potassium channel",
author = "Ewart, {Marie Ann} and Azizah Ugusman and Anisha Vishwanath and Almabrouk, {Tarek A M} and Husam Alganga and Katwan, {Omar J.} and Pavlina Hubanova and Susan Currie and Simon Kennedy",
year = "2017",
month = "4",
day = "1",
doi = "10.1159/000461581",
language = "English",
pages = "68--78",
journal = "Journal of Vascular Research",
issn = "1018-1172",
publisher = "S. Karger AG",

}

TY - JOUR

T1 - Changes in IP3 Receptor Expression and Function in Aortic Smooth Muscle of Atherosclerotic Mice

AU - Ewart, Marie Ann

AU - Ugusman, Azizah

AU - Vishwanath, Anisha

AU - Almabrouk, Tarek A M

AU - Alganga, Husam

AU - Katwan, Omar J.

AU - Hubanova, Pavlina

AU - Currie, Susan

AU - Kennedy, Simon

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Peroxynitrite is an endothelium-independent vasodilator that induces relaxation via membrane hyperpolarization. The activation of IP3 receptors triggers the opening of potassium channels and hyperpolarization. Previously we found that relaxation to peroxynitrite was maintained during the development of atherosclerosis due to changes in the expression of calcium-regulatory proteins. In this study we investigated: (1) the mechanism of peroxynitrite-induced relaxation in the mouse aorta, (2) the effect of atherosclerosis on relaxation to peroxynitrite and other vasodilators, and (3) the effect of atherosclerosis on the expression and function of the IP3 receptor. Aortic function was studied using wire myography, and atherosclerosis was induced by fat-feeding ApoE-/- mice. The expression of IP3 receptors was studied using Western blotting and immunohistochemistry. Relaxation to peroxynitrite was attenuated by the IP3 antagonists 2-APB and xestospongin C and also the Kv channel blocker 4-aminopyridine (4-AP). Atherosclerosis attenuated vasodilation to cromakalim and the AMPK activator A769662 but not peroxynitrite. Relaxation was attenuated to a greater extent by 2-APB in atherosclerotic aortae despite the reduced expression of IP3 receptors. 4-AP was less effective in ApoE-/- mice fat-fed for 4 months. Peroxynitrite relaxation involves an IP3-induced calcium release and KV channel activation. This mechanism becomes less important as atherosclerosis develops, and relaxation to peroxynitrite may be maintained by increased calcium extrusion.

AB - Peroxynitrite is an endothelium-independent vasodilator that induces relaxation via membrane hyperpolarization. The activation of IP3 receptors triggers the opening of potassium channels and hyperpolarization. Previously we found that relaxation to peroxynitrite was maintained during the development of atherosclerosis due to changes in the expression of calcium-regulatory proteins. In this study we investigated: (1) the mechanism of peroxynitrite-induced relaxation in the mouse aorta, (2) the effect of atherosclerosis on relaxation to peroxynitrite and other vasodilators, and (3) the effect of atherosclerosis on the expression and function of the IP3 receptor. Aortic function was studied using wire myography, and atherosclerosis was induced by fat-feeding ApoE-/- mice. The expression of IP3 receptors was studied using Western blotting and immunohistochemistry. Relaxation to peroxynitrite was attenuated by the IP3 antagonists 2-APB and xestospongin C and also the Kv channel blocker 4-aminopyridine (4-AP). Atherosclerosis attenuated vasodilation to cromakalim and the AMPK activator A769662 but not peroxynitrite. Relaxation was attenuated to a greater extent by 2-APB in atherosclerotic aortae despite the reduced expression of IP3 receptors. 4-AP was less effective in ApoE-/- mice fat-fed for 4 months. Peroxynitrite relaxation involves an IP3-induced calcium release and KV channel activation. This mechanism becomes less important as atherosclerosis develops, and relaxation to peroxynitrite may be maintained by increased calcium extrusion.

KW - Aorta

KW - Atherosclerosis

KW - IP3 receptor

KW - Peroxynitrite

KW - Potassium channel

UR - http://www.scopus.com/inward/record.url?scp=85017137985&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017137985&partnerID=8YFLogxK

U2 - 10.1159/000461581

DO - 10.1159/000461581

M3 - Article

C2 - 28365690

AN - SCOPUS:85017137985

SP - 68

EP - 78

JO - Journal of Vascular Research

JF - Journal of Vascular Research

SN - 1018-1172

ER -