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

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.

Interrelated Cathepsin S-Lowering and LDL Subclass Profile Improvements Induced by Atorvastatin in the Plasma of Stable Angina Patients

“…The absence of atorvastatin-induced lowering of the CTSS expression, as assessed non-invasively according to a plasma mRNA analysis, is contradictory to the decreased gene expression observed in the myocardium of apoE −/− mice after 32 weeks of simvastatin treatment 12) but in line with the findings of our previous study in which atorvastatin-treated patients with coronary atherosclerosis had a higher CTSS expression than healthy subjects 13) . In the present study, despite the lack of changes in the gene expression, atorvastatin lowered the extracellular CTSS protein concentrations and enzyme activity.…”

“…Current data on the effects of statins on CTSS are scarce. One study conducted in humans indicated that statin treatment does not change the CTSS activity in the wall of abdominal aortic aneurysms 11) , while another study revealed that the expression of CTSS mRNA and protein was significantly increased in the myocardium of apoE −/− mice fed a Western-style diet and that simvastatin decreases the levels of CTSS mRNA and protein after 32 weeks of treatment 12) . In our previous study 13) , a plasma mRNA analysis revealed that patients with coronary atherosclerosis have a much higher CTSS expression than control subjects, despite receiving statin treatment.…”

Cysteine Protease Cathepsins in Atherosclerosis-Based Vascular Disease and Its Complications

“…Strikingly, simvastatin can inhibited cardiac hypertrophy and fibrosis in ApoE Ϫ/Ϫ mice fed a high-fat diet via a reduction of cathepsin S and MMP-9 expressions in association with increasing peroxisome proliferator-activated receptor-␣ and -␥ expressions. 92 …”

Original Research: Atorvastatin prevents rat cardiomyocyte hypertrophy induced by parathyroid hormone 1–34 associated with the Ras-ERK signaling

“…a P < 0.05 versus NC group, b P < 0.05 versus PTH group, c P < 0.05 versus PTH þ Ator group. NC, normal control; PTH, parathyroid hormone; MVA, mevalonic acid, the activator of Ras; FTI, farnesyl transferase inhibitors, the inhibitor of Ras activated receptor a (PPAR a) and PPAR c, 31 as well as preventing the activation of nuclear factor (NF)-kB. 32 However, the majority of studies suggested that the suppressive effect of statins on CMH was associated with the inhibition of MVA pathway and small GTPases activity.…”