Amlodipine and Atorvastatin Improved Hypertensive Cardiac Remodeling through Regulation of MMPs/TIMPs in SHR Rats

Abstract

Background: MMPs/TIMPs system is well known to play important roles in pressure overload-induced cardiac remodeling, and Amlodipine and Atorvastatin have been showed to exert favourable protective effects on cardiovascular disease, however, it is not clear whether Amlodipine and Atorvastatin can improve hypertensive cardiac remodeling and whether the MMPs/TIMPs system is involved. The present study aims to answer these questions. Methods: 36 weeks old male spontaneous hypertension (SHR) rats were randomly divided into four groups: 1). SHR control group, 2). Amlodipine alone (10 mg/kg/d) group, 3). Atorvastatin alone (10 mg/kg/d) group, 4).Combination of Amlodipine and Atorvastatin (10 mg/kg/d for each) group. Same gender, weight and age of Wistar-Kyoto (WKY) rats with normal blood pressure were used as normal control. Drugs were administered by oral gavage over 12 weeks. The blood pressure and left ventricle mass index were measured. Enzyme activity of MMP-2 and MMP-9 was assessed with Gelatin zymography. MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA and protein expression was studied by RT-PCR and Western blot. Single factor ANOVA and LSD-t test were used in statistical analysis. Results: Treatment with Amlodipine alone or combination with atorvastatin significantly decreased blood pressure, left ventricle mass index in SHR rats (P < 0.05 for both). Compared with WKY rats, the myocardial levels of MMP-2, MMP-9 mRNA, protein and enzyme activity were significantly increased (P<0.05). Amlodipine alone, Atorvastatin alone, and combination of the two all reduced MMP-2 and MMP-9 mRNA, protein and enzyme activity, with the best effects seen in the combination. Compared with WKY rats, the myocardial levels of TIMP-1 mRNA and protein were significantly increased (P<0.05), however, there was no difference in levels of TIMP-2. Neither Amlodipine alone, Atorvastatin alone, nor combination of the two drugs significantly affect the expression of TIMP-1 or TIMP-2. Conclusion: Amlodipine and Atorvastatin could improve ventricular remodeling in SHR rats through intervention with the imbalance of MMP-2/TIMP-2 and MMP-9/TIMP-1 system.

Atorvastatin Prevents Myocardial Fibrosis in Spontaneous Hypertension via Interleukin-6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3)/Endothelin-1 (ET-1) Pathway

“…As early as 2001 [13], Takemoto et.al raised that statins could be used as antioxidant therapy to prevent cardiac myocyte hypertrophy. A latest report [14] also showed that Ato helped improve hypertensive cardiac remodeling by Regulating MMPs/TIMPs in SHR Rats. Similarly, a study [4] of radiation-induced cardiac fibrosis revealed an obvious therapeutic effect of Ato, which also partly supports our findings.…”

“…The SHR group (n=8) and WKY group (n=8) received 1 mL distilled water/day by gavage. The Ato-treated SHR group (n=8) received a low dosage of 10 mg/kg/day [12] i.g. The Ato-treated SHR group (n=8) received a medium dosage of 25 mg/kg/day i.g.…”

Atorvastatin Calcium Inhibits PDGF-ββ-Induced Proliferation and Migration of VSMCs Through the G0/G1 Cell Cycle Arrest and Suppression of Activated PDGFRβ-PI3K-Akt Signaling Cascade

“…Previous studies showed that MMPs, specifically MMP-2 and MMP-9, were activated rapidly following vascular injury [36-38] and played an important role in disrupting the ECM in VSMCs [37, 39]. Degradation of the ECM promoted VSMC migration from the media of arterial walls to the intimal space, where VSMCs secreted more ECM products, progressively resulting in restenosis and neointima formation [40, 41].…”

Combination of serum TIMP-3, CA125, and NT-proBNP in predicting ventricular remodeling in patients with heart failure following acute myocardial infarction

“…TIMP is a type of MMP inhibitor, and MMP/TIMP imbalance can cause abnormal extracardiomyocyte collagen accumulation, which leads to ventricular stiffening and myocardial fibrosis and prevents myocardial relaxation and contraction. TIMPs can block MMPs from binding to their substrates and inhibit their activity, which subsequently delays the progression of ventricular remodeling (12,13). TIMP-3 is a member of the TIMP family and is a specific non-soluble protein that inhibits MMP activity.…”