Effect of testosterone on inflammatory markers in the development of early atherogenesis in the testicular-feminized mouse model

Daniel M. Kelly, Donna J Sellers, M Nicola Woodroofe, T. Hugh Jones, Kevin S. Channer

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

Background. 

Low levels of serum testosterone in men are associated with cardiovascular disease. Clinical studies show that testosterone replacement therapy (TRT) can improve symptoms of cardiovascular disease and reduce the inflammatory burden evident in atherosclerosis. 

Aim. 

We used an in vivo animal model to determine whether testosterone influences mediators of vascular inflammation as part of its beneficial effects on atherogenesis. 

Methods. 

Testicular-feminized (Tfm) mice, which express low endogenous testosterone and a non-functional androgen receptor (AR), were used to assess the effect of androgen status on atheroma formation, serum lipids, and inflammatory mediators. Tfm mice were fed a high-cholesterol diet, received saline or physiological (TRT), and were compared to saline-treated XY littermates. 

Results. 

A total of 28 weeks of high-cholesterol diet caused fatty streak formation in the aortic root of XY littermates and Tfm mice, an effect significantly amplified in Tfm mice. Tfm mice on normal diet showed elevated serum tumor necrosis factor-α (TFN-α) and interleukin-6 compared to XY littermates. High-cholesterol diet induced increased monocyte chemoattractant protein-1 (MCP-1) in Tfm mice, and TFN-α and MCP-1 in XY littermates. TRT reduced fatty streak formation and serum interleukin-6 in Tfm mice but had no significant effects on lipid profiles. Monocyte/macrophage staining indicated local inflammation in aortic root fatty streak areas of all mice, with TRT reducing local inflammation through plaque reduction in Tfm mice. Fractalkine (CX(3)CL1) and its receptor (CX(3)CR1) were present in fatty streaks of all mice fed a high-cholesterol diet, independent of androgen status. 

Conclusion. 

These results are consistent with AR-dependent and AR-independent anti-inflammatory actions of testosterone in atheroprotection, although the local anti-inflammatory mechanisms via which testosterone acts remain unknown.

Original languageEnglish
Pages (from-to)125-138
Number of pages14
JournalEndocrine Research
Volume38
Issue number3
DOIs
Publication statusE-pub ahead of print - 20 Nov 2012
Externally publishedYes

Fingerprint

Testosterone
Atherosclerosis
Diet
Androgen Receptors
Cholesterol
Serum
Androgens
Interleukin-6
Anti-Inflammatory Agents
Cardiovascular Diseases
Chemokine CX3CL1
Inflammation
Lipids
Inflammation Mediators
Chemokine CCL2
Atherosclerotic Plaques
Therapeutics
Blood Vessels
Monocytes
Animal Models

Cite this

Kelly, Daniel M. ; Sellers, Donna J ; Woodroofe, M Nicola ; Jones, T. Hugh ; Channer, Kevin S. / Effect of testosterone on inflammatory markers in the development of early atherogenesis in the testicular-feminized mouse model. In: Endocrine Research. 2012 ; Vol. 38, No. 3. pp. 125-138.
@article{1a84ef40484341eca2773432cbc8a0f9,
title = "Effect of testosterone on inflammatory markers in the development of early atherogenesis in the testicular-feminized mouse model",
abstract = "Background. Low levels of serum testosterone in men are associated with cardiovascular disease. Clinical studies show that testosterone replacement therapy (TRT) can improve symptoms of cardiovascular disease and reduce the inflammatory burden evident in atherosclerosis. Aim. We used an in vivo animal model to determine whether testosterone influences mediators of vascular inflammation as part of its beneficial effects on atherogenesis. Methods. Testicular-feminized (Tfm) mice, which express low endogenous testosterone and a non-functional androgen receptor (AR), were used to assess the effect of androgen status on atheroma formation, serum lipids, and inflammatory mediators. Tfm mice were fed a high-cholesterol diet, received saline or physiological (TRT), and were compared to saline-treated XY littermates. Results. A total of 28 weeks of high-cholesterol diet caused fatty streak formation in the aortic root of XY littermates and Tfm mice, an effect significantly amplified in Tfm mice. Tfm mice on normal diet showed elevated serum tumor necrosis factor-α (TFN-α) and interleukin-6 compared to XY littermates. High-cholesterol diet induced increased monocyte chemoattractant protein-1 (MCP-1) in Tfm mice, and TFN-α and MCP-1 in XY littermates. TRT reduced fatty streak formation and serum interleukin-6 in Tfm mice but had no significant effects on lipid profiles. Monocyte/macrophage staining indicated local inflammation in aortic root fatty streak areas of all mice, with TRT reducing local inflammation through plaque reduction in Tfm mice. Fractalkine (CX(3)CL1) and its receptor (CX(3)CR1) were present in fatty streaks of all mice fed a high-cholesterol diet, independent of androgen status. Conclusion. These results are consistent with AR-dependent and AR-independent anti-inflammatory actions of testosterone in atheroprotection, although the local anti-inflammatory mechanisms via which testosterone acts remain unknown.",
author = "Kelly, {Daniel M.} and Sellers, {Donna J} and Woodroofe, {M Nicola} and Jones, {T. Hugh} and Channer, {Kevin S.}",
year = "2012",
month = "11",
day = "20",
doi = "10.3109/07435800.2012.735307",
language = "English",
volume = "38",
pages = "125--138",
journal = "Endocrine Research Communications",
issn = "0743-5800",
publisher = "Informa Healthcare USA",
number = "3",

}

Effect of testosterone on inflammatory markers in the development of early atherogenesis in the testicular-feminized mouse model. / Kelly, Daniel M.; Sellers, Donna J; Woodroofe, M Nicola; Jones, T. Hugh; Channer, Kevin S.

In: Endocrine Research, Vol. 38, No. 3, 20.11.2012, p. 125-138.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effect of testosterone on inflammatory markers in the development of early atherogenesis in the testicular-feminized mouse model

AU - Kelly, Daniel M.

AU - Sellers, Donna J

AU - Woodroofe, M Nicola

AU - Jones, T. Hugh

AU - Channer, Kevin S.

PY - 2012/11/20

Y1 - 2012/11/20

N2 - Background. Low levels of serum testosterone in men are associated with cardiovascular disease. Clinical studies show that testosterone replacement therapy (TRT) can improve symptoms of cardiovascular disease and reduce the inflammatory burden evident in atherosclerosis. Aim. We used an in vivo animal model to determine whether testosterone influences mediators of vascular inflammation as part of its beneficial effects on atherogenesis. Methods. Testicular-feminized (Tfm) mice, which express low endogenous testosterone and a non-functional androgen receptor (AR), were used to assess the effect of androgen status on atheroma formation, serum lipids, and inflammatory mediators. Tfm mice were fed a high-cholesterol diet, received saline or physiological (TRT), and were compared to saline-treated XY littermates. Results. A total of 28 weeks of high-cholesterol diet caused fatty streak formation in the aortic root of XY littermates and Tfm mice, an effect significantly amplified in Tfm mice. Tfm mice on normal diet showed elevated serum tumor necrosis factor-α (TFN-α) and interleukin-6 compared to XY littermates. High-cholesterol diet induced increased monocyte chemoattractant protein-1 (MCP-1) in Tfm mice, and TFN-α and MCP-1 in XY littermates. TRT reduced fatty streak formation and serum interleukin-6 in Tfm mice but had no significant effects on lipid profiles. Monocyte/macrophage staining indicated local inflammation in aortic root fatty streak areas of all mice, with TRT reducing local inflammation through plaque reduction in Tfm mice. Fractalkine (CX(3)CL1) and its receptor (CX(3)CR1) were present in fatty streaks of all mice fed a high-cholesterol diet, independent of androgen status. Conclusion. These results are consistent with AR-dependent and AR-independent anti-inflammatory actions of testosterone in atheroprotection, although the local anti-inflammatory mechanisms via which testosterone acts remain unknown.

AB - Background. Low levels of serum testosterone in men are associated with cardiovascular disease. Clinical studies show that testosterone replacement therapy (TRT) can improve symptoms of cardiovascular disease and reduce the inflammatory burden evident in atherosclerosis. Aim. We used an in vivo animal model to determine whether testosterone influences mediators of vascular inflammation as part of its beneficial effects on atherogenesis. Methods. Testicular-feminized (Tfm) mice, which express low endogenous testosterone and a non-functional androgen receptor (AR), were used to assess the effect of androgen status on atheroma formation, serum lipids, and inflammatory mediators. Tfm mice were fed a high-cholesterol diet, received saline or physiological (TRT), and were compared to saline-treated XY littermates. Results. A total of 28 weeks of high-cholesterol diet caused fatty streak formation in the aortic root of XY littermates and Tfm mice, an effect significantly amplified in Tfm mice. Tfm mice on normal diet showed elevated serum tumor necrosis factor-α (TFN-α) and interleukin-6 compared to XY littermates. High-cholesterol diet induced increased monocyte chemoattractant protein-1 (MCP-1) in Tfm mice, and TFN-α and MCP-1 in XY littermates. TRT reduced fatty streak formation and serum interleukin-6 in Tfm mice but had no significant effects on lipid profiles. Monocyte/macrophage staining indicated local inflammation in aortic root fatty streak areas of all mice, with TRT reducing local inflammation through plaque reduction in Tfm mice. Fractalkine (CX(3)CL1) and its receptor (CX(3)CR1) were present in fatty streaks of all mice fed a high-cholesterol diet, independent of androgen status. Conclusion. These results are consistent with AR-dependent and AR-independent anti-inflammatory actions of testosterone in atheroprotection, although the local anti-inflammatory mechanisms via which testosterone acts remain unknown.

U2 - 10.3109/07435800.2012.735307

DO - 10.3109/07435800.2012.735307

M3 - Article

VL - 38

SP - 125

EP - 138

JO - Endocrine Research Communications

JF - Endocrine Research Communications

SN - 0743-5800

IS - 3

ER -