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


CONCLUSIONS
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.
Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang City, China.
Jingchao
J
Lu
Jie
J
Hao
Hong
H
Du
Bing
B
Xiao
Yue
Y
Li
Xiuchun
X
Yang
Wei
W
Cui
D017311:Amlodipine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D000069059:Atorvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D004338:Drug Combinations; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*
D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D004338:Drug Combinations; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D017311:Amlodipine; D000069059:Atorvastatin; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9