Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury

Ye Song, Jianxun Wang, Van Li, Yibo Du, Gavin E. Arteel, Jack T. Saari, Yujian Kang, Lu Cai

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Oxidative stress is involved in the pathogenesis of diabetes and its cardiovascular complications. Metallothionein (MT), a stress-response protein, is significantly increased in the liver and kidney of diabetic animals. We examined whether diabetes also induces cardiac MT synthesis through oxidative damage and whether MT overexpression protects the heart from injury. Diabetes was induced in mice by single injection of streptozotocin (STZ), and cardiac MT mRNA and protein levels were measured 2 weeks and 2 months after STZ treatment. Diabetes significantly increased cardiac MT synthesis 2 weeks and 2 months after STZ treatment, with no change in cardiac metals including zinc, copper, and iron. Serum and cardiac vasopeptide endothelin and inflammatory cytokine tumor necrosis factor-α were also significantly increased in diabetic hearts, as were the ratio of oxidized to reduced glutathione and the immunohistocheniical staining of 3-nitrotyrosine and 4-hydroxynonenal. To explore the biological importance of increased MT synthesis in the heart, MT-overexpressing transgenic mice were treated with STZ and then examined 2 months later. A loss of inotropic reserve, uncovered during β-adrenergic stimulation, and the presence of cardiac fibrosis, shown by increased Sirius red staining of collagen, were evident in the wild-type diabetic mice but not in the MT-overexpressing transgenic diabetic mice. These results suggest that diabetes-induced cardiac MT expression likely associates with systemic increases in endothelin-1 and tumor necrosis factor-α and the resulting cardiac oxidative stress. Overexpressing cardiac MT significantly protects the heart from diabetes-induced injury.

Original languageEnglish (US)
Pages (from-to)17-26
Number of pages10
JournalAmerican Journal of Pathology
Volume167
Issue number1
DOIs
StatePublished - Jan 1 2005

Fingerprint

Metallothionein
Streptozocin
Wounds and Injuries
Transgenic Mice
Oxidative Stress
Tumor Necrosis Factor-alpha
Heart Injuries
Staining and Labeling
Endothelins
Endothelin-1
Heat-Shock Proteins
Adrenergic Agents
Glutathione
Zinc
Copper
Fibrosis
Collagen
Iron
Metals
Cytokines

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury. / Song, Ye; Wang, Jianxun; Li, Van; Du, Yibo; Arteel, Gavin E.; Saari, Jack T.; Kang, Yujian; Cai, Lu.

In: American Journal of Pathology, Vol. 167, No. 1, 01.01.2005, p. 17-26.

Research output: Contribution to journalArticle

Song, Ye ; Wang, Jianxun ; Li, Van ; Du, Yibo ; Arteel, Gavin E. ; Saari, Jack T. ; Kang, Yujian ; Cai, Lu. / Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury. In: American Journal of Pathology. 2005 ; Vol. 167, No. 1. pp. 17-26.
@article{451416b9e9244ddab35c11ee55832155,
title = "Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury",
abstract = "Oxidative stress is involved in the pathogenesis of diabetes and its cardiovascular complications. Metallothionein (MT), a stress-response protein, is significantly increased in the liver and kidney of diabetic animals. We examined whether diabetes also induces cardiac MT synthesis through oxidative damage and whether MT overexpression protects the heart from injury. Diabetes was induced in mice by single injection of streptozotocin (STZ), and cardiac MT mRNA and protein levels were measured 2 weeks and 2 months after STZ treatment. Diabetes significantly increased cardiac MT synthesis 2 weeks and 2 months after STZ treatment, with no change in cardiac metals including zinc, copper, and iron. Serum and cardiac vasopeptide endothelin and inflammatory cytokine tumor necrosis factor-α were also significantly increased in diabetic hearts, as were the ratio of oxidized to reduced glutathione and the immunohistocheniical staining of 3-nitrotyrosine and 4-hydroxynonenal. To explore the biological importance of increased MT synthesis in the heart, MT-overexpressing transgenic mice were treated with STZ and then examined 2 months later. A loss of inotropic reserve, uncovered during β-adrenergic stimulation, and the presence of cardiac fibrosis, shown by increased Sirius red staining of collagen, were evident in the wild-type diabetic mice but not in the MT-overexpressing transgenic diabetic mice. These results suggest that diabetes-induced cardiac MT expression likely associates with systemic increases in endothelin-1 and tumor necrosis factor-α and the resulting cardiac oxidative stress. Overexpressing cardiac MT significantly protects the heart from diabetes-induced injury.",
author = "Ye Song and Jianxun Wang and Van Li and Yibo Du and Arteel, {Gavin E.} and Saari, {Jack T.} and Yujian Kang and Lu Cai",
year = "2005",
month = "1",
day = "1",
doi = "10.1016/S0002-9440(10)62949-5",
language = "English (US)",
volume = "167",
pages = "17--26",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury

AU - Song, Ye

AU - Wang, Jianxun

AU - Li, Van

AU - Du, Yibo

AU - Arteel, Gavin E.

AU - Saari, Jack T.

AU - Kang, Yujian

AU - Cai, Lu

PY - 2005/1/1

Y1 - 2005/1/1

N2 - Oxidative stress is involved in the pathogenesis of diabetes and its cardiovascular complications. Metallothionein (MT), a stress-response protein, is significantly increased in the liver and kidney of diabetic animals. We examined whether diabetes also induces cardiac MT synthesis through oxidative damage and whether MT overexpression protects the heart from injury. Diabetes was induced in mice by single injection of streptozotocin (STZ), and cardiac MT mRNA and protein levels were measured 2 weeks and 2 months after STZ treatment. Diabetes significantly increased cardiac MT synthesis 2 weeks and 2 months after STZ treatment, with no change in cardiac metals including zinc, copper, and iron. Serum and cardiac vasopeptide endothelin and inflammatory cytokine tumor necrosis factor-α were also significantly increased in diabetic hearts, as were the ratio of oxidized to reduced glutathione and the immunohistocheniical staining of 3-nitrotyrosine and 4-hydroxynonenal. To explore the biological importance of increased MT synthesis in the heart, MT-overexpressing transgenic mice were treated with STZ and then examined 2 months later. A loss of inotropic reserve, uncovered during β-adrenergic stimulation, and the presence of cardiac fibrosis, shown by increased Sirius red staining of collagen, were evident in the wild-type diabetic mice but not in the MT-overexpressing transgenic diabetic mice. These results suggest that diabetes-induced cardiac MT expression likely associates with systemic increases in endothelin-1 and tumor necrosis factor-α and the resulting cardiac oxidative stress. Overexpressing cardiac MT significantly protects the heart from diabetes-induced injury.

AB - Oxidative stress is involved in the pathogenesis of diabetes and its cardiovascular complications. Metallothionein (MT), a stress-response protein, is significantly increased in the liver and kidney of diabetic animals. We examined whether diabetes also induces cardiac MT synthesis through oxidative damage and whether MT overexpression protects the heart from injury. Diabetes was induced in mice by single injection of streptozotocin (STZ), and cardiac MT mRNA and protein levels were measured 2 weeks and 2 months after STZ treatment. Diabetes significantly increased cardiac MT synthesis 2 weeks and 2 months after STZ treatment, with no change in cardiac metals including zinc, copper, and iron. Serum and cardiac vasopeptide endothelin and inflammatory cytokine tumor necrosis factor-α were also significantly increased in diabetic hearts, as were the ratio of oxidized to reduced glutathione and the immunohistocheniical staining of 3-nitrotyrosine and 4-hydroxynonenal. To explore the biological importance of increased MT synthesis in the heart, MT-overexpressing transgenic mice were treated with STZ and then examined 2 months later. A loss of inotropic reserve, uncovered during β-adrenergic stimulation, and the presence of cardiac fibrosis, shown by increased Sirius red staining of collagen, were evident in the wild-type diabetic mice but not in the MT-overexpressing transgenic diabetic mice. These results suggest that diabetes-induced cardiac MT expression likely associates with systemic increases in endothelin-1 and tumor necrosis factor-α and the resulting cardiac oxidative stress. Overexpressing cardiac MT significantly protects the heart from diabetes-induced injury.

UR - http://www.scopus.com/inward/record.url?scp=21244502594&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=21244502594&partnerID=8YFLogxK

U2 - 10.1016/S0002-9440(10)62949-5

DO - 10.1016/S0002-9440(10)62949-5

M3 - Article

VL - 167

SP - 17

EP - 26

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 1

ER -