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Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a "Western-style diet" by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels.

Qin YW, Ye P, He JQ, Sheng L, Wang LY, Du J - Acta Pharmacol. Sin. (2010)

Bottom Line: The simvastatin treatment group showed significantly reduced LV wall thickness, myocardial cell diameters and LV collagen content at 40 weeks when compared with the control group (P<0.05).Furthermore, treatment with simvastatin also significantly inhibited the mRNA and protein expressions of MMP-9 and Cat S as well as increased the mRNA and protein expressions of PPAR alpha and PPAR gamma at 32 and 40 weeks compared with the control group (P<0.05).Simvastatin treatment inhibits the development of cardiac hypertrophy and fibrosis, and this effect may be mediated through increased levels of PPAR alpha and PPAR gamma and reduced levels of TC, MMP-9, and Cat S.

View Article: PubMed Central - PubMed

Affiliation: Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China.

ABSTRACT

Aim: The examine the cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice (ApoE-/- mice) fed a "Western-style diet" and the effect of simvastatin intervention.

Methods: Male ApoE-/- mice (n=36) were fed a "Western-style diet" from the age of 8 weeks. After 16 weeks, they were randomly given either simvastatin (25 mg·kg⁻¹·d⁻¹) or normal saline (control group) by gavage for 8, 16, or 24 weeks. The left ventricular (LV) wall thickness and diameter of the myocardial cells were determined with Hematoxylin-Eosin stain, and the level of fibrosis of the myocardial matrix was assessed with Masson stain. Real-time quantitative polymerase chain reaction and Western blotting analysis were used to determine the mRNA and protein expression of matrix metalloproteinase-9 (MMP-9), Cathepsin S (Cat S), and the peroxisome proliferator-activated receptors (PPARs) in the myocardium of ApoE-/- mice.

Results: ApoE-/- mice fed a "Western-style diet" showed an significant age-dependent increase in total cholesterol (TC), LV wall thickness, myocardial cell diameter and LV collagen content (P<0.05). The simvastatin treatment group showed significantly reduced LV wall thickness, myocardial cell diameters and LV collagen content at 40 weeks when compared with the control group (P<0.05). Furthermore, treatment with simvastatin also significantly inhibited the mRNA and protein expressions of MMP-9 and Cat S as well as increased the mRNA and protein expressions of PPAR alpha and PPAR gamma at 32 and 40 weeks compared with the control group (P<0.05).

Conclusion: ApoE-/- mice fed a "Western-style diet" had cardiac hypertrophy and fibrosis, which worsened with age. Simvastatin treatment inhibits the development of cardiac hypertrophy and fibrosis, and this effect may be mediated through increased levels of PPAR alpha and PPAR gamma and reduced levels of TC, MMP-9, and Cat S.

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Related in: MedlinePlus

Serum and myocardium TC levels after control and simvastatin treatment in ApoE−/− mice fed a “Western-style diet”. (A) Serum TC levels. (B) Myocardial TC levels. The control group showed an age-dependent increase in serum and myocardial TC levels, which was significantly inhibited by simvastatin at 24, 32, and 40 weeks. The results are given as means±SD. bP<0.05, significant difference between the control and simvastatin groups of the same age. eP<0.05, significant difference between the control groups of different ages.
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fig3: Serum and myocardium TC levels after control and simvastatin treatment in ApoE−/− mice fed a “Western-style diet”. (A) Serum TC levels. (B) Myocardial TC levels. The control group showed an age-dependent increase in serum and myocardial TC levels, which was significantly inhibited by simvastatin at 24, 32, and 40 weeks. The results are given as means±SD. bP<0.05, significant difference between the control and simvastatin groups of the same age. eP<0.05, significant difference between the control groups of different ages.

Mentions: TC levels in the serum and myocardium were measured to investigate a possible relationship between cardiac hypertrophy and lipid levels. There was a significant age-related increase in the levels of serum and myocardium TC in the control ApoE−/− mice (P<0.05). Serum TC levels were lower in the simvastatin group than in the control group (12.80±0.33 mmol/L vs 16.89±0.24 mmol/L at 24 weeks, 14.96±0.25 mmol/L vs 19.56±0.36 mmol/L at 32 weeks, 18.54±0.18 mmol/L vs 23.09±0.36 mmol/L at 40 weeks; P<0.05). The myocardial TC levels were also lower in the simvastatin group than in the control group (3.65±0.33 nmol/mg vs 4.36±0.16 nmol/mg at 24 weeks, 5.21±0.15 nmol/mg vs 6.83±0.38 nmol/mg at 32 weeks, 7.36±0.23 nmol/mg vs 10.37±0.28 nmol/mg at the 40 weeks; P<0.05) (Figure 3).


Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a "Western-style diet" by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels.

Qin YW, Ye P, He JQ, Sheng L, Wang LY, Du J - Acta Pharmacol. Sin. (2010)

Serum and myocardium TC levels after control and simvastatin treatment in ApoE−/− mice fed a “Western-style diet”. (A) Serum TC levels. (B) Myocardial TC levels. The control group showed an age-dependent increase in serum and myocardial TC levels, which was significantly inhibited by simvastatin at 24, 32, and 40 weeks. The results are given as means±SD. bP<0.05, significant difference between the control and simvastatin groups of the same age. eP<0.05, significant difference between the control groups of different ages.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4012913&req=5

fig3: Serum and myocardium TC levels after control and simvastatin treatment in ApoE−/− mice fed a “Western-style diet”. (A) Serum TC levels. (B) Myocardial TC levels. The control group showed an age-dependent increase in serum and myocardial TC levels, which was significantly inhibited by simvastatin at 24, 32, and 40 weeks. The results are given as means±SD. bP<0.05, significant difference between the control and simvastatin groups of the same age. eP<0.05, significant difference between the control groups of different ages.
Mentions: TC levels in the serum and myocardium were measured to investigate a possible relationship between cardiac hypertrophy and lipid levels. There was a significant age-related increase in the levels of serum and myocardium TC in the control ApoE−/− mice (P<0.05). Serum TC levels were lower in the simvastatin group than in the control group (12.80±0.33 mmol/L vs 16.89±0.24 mmol/L at 24 weeks, 14.96±0.25 mmol/L vs 19.56±0.36 mmol/L at 32 weeks, 18.54±0.18 mmol/L vs 23.09±0.36 mmol/L at 40 weeks; P<0.05). The myocardial TC levels were also lower in the simvastatin group than in the control group (3.65±0.33 nmol/mg vs 4.36±0.16 nmol/mg at 24 weeks, 5.21±0.15 nmol/mg vs 6.83±0.38 nmol/mg at 32 weeks, 7.36±0.23 nmol/mg vs 10.37±0.28 nmol/mg at the 40 weeks; P<0.05) (Figure 3).

Bottom Line: The simvastatin treatment group showed significantly reduced LV wall thickness, myocardial cell diameters and LV collagen content at 40 weeks when compared with the control group (P<0.05).Furthermore, treatment with simvastatin also significantly inhibited the mRNA and protein expressions of MMP-9 and Cat S as well as increased the mRNA and protein expressions of PPAR alpha and PPAR gamma at 32 and 40 weeks compared with the control group (P<0.05).Simvastatin treatment inhibits the development of cardiac hypertrophy and fibrosis, and this effect may be mediated through increased levels of PPAR alpha and PPAR gamma and reduced levels of TC, MMP-9, and Cat S.

View Article: PubMed Central - PubMed

Affiliation: Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China.

ABSTRACT

Aim: The examine the cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice (ApoE-/- mice) fed a "Western-style diet" and the effect of simvastatin intervention.

Methods: Male ApoE-/- mice (n=36) were fed a "Western-style diet" from the age of 8 weeks. After 16 weeks, they were randomly given either simvastatin (25 mg·kg⁻¹·d⁻¹) or normal saline (control group) by gavage for 8, 16, or 24 weeks. The left ventricular (LV) wall thickness and diameter of the myocardial cells were determined with Hematoxylin-Eosin stain, and the level of fibrosis of the myocardial matrix was assessed with Masson stain. Real-time quantitative polymerase chain reaction and Western blotting analysis were used to determine the mRNA and protein expression of matrix metalloproteinase-9 (MMP-9), Cathepsin S (Cat S), and the peroxisome proliferator-activated receptors (PPARs) in the myocardium of ApoE-/- mice.

Results: ApoE-/- mice fed a "Western-style diet" showed an significant age-dependent increase in total cholesterol (TC), LV wall thickness, myocardial cell diameter and LV collagen content (P<0.05). The simvastatin treatment group showed significantly reduced LV wall thickness, myocardial cell diameters and LV collagen content at 40 weeks when compared with the control group (P<0.05). Furthermore, treatment with simvastatin also significantly inhibited the mRNA and protein expressions of MMP-9 and Cat S as well as increased the mRNA and protein expressions of PPAR alpha and PPAR gamma at 32 and 40 weeks compared with the control group (P<0.05).

Conclusion: ApoE-/- mice fed a "Western-style diet" had cardiac hypertrophy and fibrosis, which worsened with age. Simvastatin treatment inhibits the development of cardiac hypertrophy and fibrosis, and this effect may be mediated through increased levels of PPAR alpha and PPAR gamma and reduced levels of TC, MMP-9, and Cat S.

Show MeSH
Related in: MedlinePlus