Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice

Young Eun Cho, Aninda Basu, Anzhi Dai, Michael Heldak, Ayako Makino

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Endothelial cell (EC) dysfunction is implicated in cardiovascular diseases, including diabetes. The decrease in nitric oxide (NO) bioavailability is the hallmark of endothelial dysfunction, and it leads to attenuated vascular relaxation and atherosclerosis followed by a decrease in blood flow. In the heart, decreased coronary blood flow is responsible for insufficient oxygen supply to cardiomyocytes and, subsequently, increases the incidence of cardiac ischemia. In this study we investigate whether and how reactive oxygen species (ROS) in mitochondria contribute to coronary endothelial dysfunction in type 2 diabetic (T2D) mice. T2D was induced in mice by a high-fat diet combined with a single injection of low-dose streptozotocin. ACh-induced vascular relaxation was significantly attenuated in coronary arteries (CAs) from T2D mice compared with controls. The pharmacological approach reveals that NO-dependent, but not hyperpolarization- or prostacyclin-dependent, relaxation was decreased in CAs from T2D mice. Attenuated ACh-induced relaxation in CAs from T2D mice was restored toward control level by treatment with mitoTempol (a mitochondria-specific O2- scavenger). Coronary ECs isolated from T2D mice exhibited a significant increase in mitochondrial ROS concentration and decrease in SOD2 protein expression compared with coronary ECs isolated from control mice. Furthermore, protein ubiq-uitination of SOD2 was significantly increased in coronary ECs isolated from T2D mice. These results suggest that augmented SOD2 ubiquitination leads to the increase in mitochondrial ROS concentration in coronary ECs from T2D mice and attenuates coronary vascular relaxation in T2D mice.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume305
Issue number10
DOIs
StatePublished - Nov 15 2013
Externally publishedYes

Fingerprint

Reactive Oxygen Species
Blood Vessels
Coronary Vessels
Mitochondria
Nitric Oxide
Ubiquitination
High Fat Diet
Epoprostenol
Streptozocin
Cardiac Myocytes
Biological Availability
Atherosclerosis
Cardiovascular Diseases
Ischemia
Endothelial Cells
Pharmacology
Oxygen
Injections
Incidence

Keywords

  • Diabetic vascular complication
  • Hyperglycemia
  • Posttranslational modification
  • Ubiquitin-proteasome system

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

Cite this

Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice. / Cho, Young Eun; Basu, Aninda; Dai, Anzhi; Heldak, Michael; Makino, Ayako.

In: American Journal of Physiology - Cell Physiology, Vol. 305, No. 10, 15.11.2013.

Research output: Contribution to journalArticle

@article{80ba86fba138469c886a8b89d06dc6c9,
title = "Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice",
abstract = "Endothelial cell (EC) dysfunction is implicated in cardiovascular diseases, including diabetes. The decrease in nitric oxide (NO) bioavailability is the hallmark of endothelial dysfunction, and it leads to attenuated vascular relaxation and atherosclerosis followed by a decrease in blood flow. In the heart, decreased coronary blood flow is responsible for insufficient oxygen supply to cardiomyocytes and, subsequently, increases the incidence of cardiac ischemia. In this study we investigate whether and how reactive oxygen species (ROS) in mitochondria contribute to coronary endothelial dysfunction in type 2 diabetic (T2D) mice. T2D was induced in mice by a high-fat diet combined with a single injection of low-dose streptozotocin. ACh-induced vascular relaxation was significantly attenuated in coronary arteries (CAs) from T2D mice compared with controls. The pharmacological approach reveals that NO-dependent, but not hyperpolarization- or prostacyclin-dependent, relaxation was decreased in CAs from T2D mice. Attenuated ACh-induced relaxation in CAs from T2D mice was restored toward control level by treatment with mitoTempol (a mitochondria-specific O2- scavenger). Coronary ECs isolated from T2D mice exhibited a significant increase in mitochondrial ROS concentration and decrease in SOD2 protein expression compared with coronary ECs isolated from control mice. Furthermore, protein ubiq-uitination of SOD2 was significantly increased in coronary ECs isolated from T2D mice. These results suggest that augmented SOD2 ubiquitination leads to the increase in mitochondrial ROS concentration in coronary ECs from T2D mice and attenuates coronary vascular relaxation in T2D mice.",
keywords = "Diabetic vascular complication, Hyperglycemia, Posttranslational modification, Ubiquitin-proteasome system",
author = "Cho, {Young Eun} and Aninda Basu and Anzhi Dai and Michael Heldak and Ayako Makino",
year = "2013",
month = "11",
day = "15",
doi = "10.1152/ajpcell.00234.2013",
language = "English (US)",
volume = "305",
journal = "American Journal of Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "10",

}

TY - JOUR

T1 - Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice

AU - Cho, Young Eun

AU - Basu, Aninda

AU - Dai, Anzhi

AU - Heldak, Michael

AU - Makino, Ayako

PY - 2013/11/15

Y1 - 2013/11/15

N2 - Endothelial cell (EC) dysfunction is implicated in cardiovascular diseases, including diabetes. The decrease in nitric oxide (NO) bioavailability is the hallmark of endothelial dysfunction, and it leads to attenuated vascular relaxation and atherosclerosis followed by a decrease in blood flow. In the heart, decreased coronary blood flow is responsible for insufficient oxygen supply to cardiomyocytes and, subsequently, increases the incidence of cardiac ischemia. In this study we investigate whether and how reactive oxygen species (ROS) in mitochondria contribute to coronary endothelial dysfunction in type 2 diabetic (T2D) mice. T2D was induced in mice by a high-fat diet combined with a single injection of low-dose streptozotocin. ACh-induced vascular relaxation was significantly attenuated in coronary arteries (CAs) from T2D mice compared with controls. The pharmacological approach reveals that NO-dependent, but not hyperpolarization- or prostacyclin-dependent, relaxation was decreased in CAs from T2D mice. Attenuated ACh-induced relaxation in CAs from T2D mice was restored toward control level by treatment with mitoTempol (a mitochondria-specific O2- scavenger). Coronary ECs isolated from T2D mice exhibited a significant increase in mitochondrial ROS concentration and decrease in SOD2 protein expression compared with coronary ECs isolated from control mice. Furthermore, protein ubiq-uitination of SOD2 was significantly increased in coronary ECs isolated from T2D mice. These results suggest that augmented SOD2 ubiquitination leads to the increase in mitochondrial ROS concentration in coronary ECs from T2D mice and attenuates coronary vascular relaxation in T2D mice.

AB - Endothelial cell (EC) dysfunction is implicated in cardiovascular diseases, including diabetes. The decrease in nitric oxide (NO) bioavailability is the hallmark of endothelial dysfunction, and it leads to attenuated vascular relaxation and atherosclerosis followed by a decrease in blood flow. In the heart, decreased coronary blood flow is responsible for insufficient oxygen supply to cardiomyocytes and, subsequently, increases the incidence of cardiac ischemia. In this study we investigate whether and how reactive oxygen species (ROS) in mitochondria contribute to coronary endothelial dysfunction in type 2 diabetic (T2D) mice. T2D was induced in mice by a high-fat diet combined with a single injection of low-dose streptozotocin. ACh-induced vascular relaxation was significantly attenuated in coronary arteries (CAs) from T2D mice compared with controls. The pharmacological approach reveals that NO-dependent, but not hyperpolarization- or prostacyclin-dependent, relaxation was decreased in CAs from T2D mice. Attenuated ACh-induced relaxation in CAs from T2D mice was restored toward control level by treatment with mitoTempol (a mitochondria-specific O2- scavenger). Coronary ECs isolated from T2D mice exhibited a significant increase in mitochondrial ROS concentration and decrease in SOD2 protein expression compared with coronary ECs isolated from control mice. Furthermore, protein ubiq-uitination of SOD2 was significantly increased in coronary ECs isolated from T2D mice. These results suggest that augmented SOD2 ubiquitination leads to the increase in mitochondrial ROS concentration in coronary ECs from T2D mice and attenuates coronary vascular relaxation in T2D mice.

KW - Diabetic vascular complication

KW - Hyperglycemia

KW - Posttranslational modification

KW - Ubiquitin-proteasome system

UR - http://www.scopus.com/inward/record.url?scp=84887580283&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887580283&partnerID=8YFLogxK

U2 - 10.1152/ajpcell.00234.2013

DO - 10.1152/ajpcell.00234.2013

M3 - Article

C2 - 23986204

AN - SCOPUS:84887580283

VL - 305

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6143

IS - 10

ER -