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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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Relative quantitative RT-PCR analysis of the mRNAs for MMP-9 (A) and Cat S (B) in the LV myocardium of the simvastatin-treated group and their corresponding age-matched controls (n=6 for each group). The control group showed an age-dependent increase in the expression of MMP-9 and Cat S mRNAs. Simvastatin significantly reduced the expression of MMP-9 and Cat S mRNAs at 32 and 40 weeks (P<0.05). The data are normalized with respect to GAPDH mRNA levels and 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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fig5: Relative quantitative RT-PCR analysis of the mRNAs for MMP-9 (A) and Cat S (B) in the LV myocardium of the simvastatin-treated group and their corresponding age-matched controls (n=6 for each group). The control group showed an age-dependent increase in the expression of MMP-9 and Cat S mRNAs. Simvastatin significantly reduced the expression of MMP-9 and Cat S mRNAs at 32 and 40 weeks (P<0.05). The data are normalized with respect to GAPDH mRNA levels and 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: Real-time PCR and Western blot analyses were performed to determine the role of MMP-9 and Cat S in cardiac hypertrophy and fibrosis in ApoE−/− mice fed with a “Western-style diet”. The expression of MMP-9 and Cat S at both the mRNA and protein levels significantly increased with age in the control mice (P<0.05). Simvastatin decreased the mRNA levels of MMP-9 and Cat S at 32 weeks and 40 weeks (Figure 5A and 5B). Similarly, the protein expression of MMP-9 and Cat S in the simvastatin-treated group decreased when compared with the control group (Figure 6).


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)

Relative quantitative RT-PCR analysis of the mRNAs for MMP-9 (A) and Cat S (B) in the LV myocardium of the simvastatin-treated group and their corresponding age-matched controls (n=6 for each group). The control group showed an age-dependent increase in the expression of MMP-9 and Cat S mRNAs. Simvastatin significantly reduced the expression of MMP-9 and Cat S mRNAs at 32 and 40 weeks (P<0.05). The data are normalized with respect to GAPDH mRNA levels and 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.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Relative quantitative RT-PCR analysis of the mRNAs for MMP-9 (A) and Cat S (B) in the LV myocardium of the simvastatin-treated group and their corresponding age-matched controls (n=6 for each group). The control group showed an age-dependent increase in the expression of MMP-9 and Cat S mRNAs. Simvastatin significantly reduced the expression of MMP-9 and Cat S mRNAs at 32 and 40 weeks (P<0.05). The data are normalized with respect to GAPDH mRNA levels and 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: Real-time PCR and Western blot analyses were performed to determine the role of MMP-9 and Cat S in cardiac hypertrophy and fibrosis in ApoE−/− mice fed with a “Western-style diet”. The expression of MMP-9 and Cat S at both the mRNA and protein levels significantly increased with age in the control mice (P<0.05). Simvastatin decreased the mRNA levels of MMP-9 and Cat S at 32 weeks and 40 weeks (Figure 5A and 5B). Similarly, the protein expression of MMP-9 and Cat S in the simvastatin-treated group decreased when compared with the control group (Figure 6).

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