Simvastatin attenuates pulmonary vascular remodelling by down-regulating matrix metalloproteinase-1 and -9 expression in a carotid artery-jugular vein shunt pulmonary hypertension model in rats.

Abstract

OBJECTIVES:

It remains controversial as to whether simvastatin has a beneficial effect on pulmonary artery hypertension. This study aimed to explore the efficacy of simvastatin on haemodynamic changes, pulmonary vascular remodelling and expression of matrix metalloproteinase-1 and -9 (MMP-1,9) in a carotid artery-jugular vein (CA-JV) shunt pulmonary artery hypertension (PAH) model in rats.

METHODS:

Thirty-six Sprague-Dawley rats were randomized into three groups: Control group, CA-JV group, and Treatment group. A pre-tricuspid systemic-pulmonary shunt from the left common carotid artery to the external jugular vein was established on the CA-JV and Treatment groups, but only ligations of both vessels were performed in Control group. Simvastatin (4 mg/kg/d) was administered to the Treatment group, and placebo to the CA-JV group. Twelve weeks later, the animals underwent a haemodynamic evaluation, followed by pulmonary tissue sampling for morphometry, quantitative real-time PCR and Western blot analysis.

RESULTS:

By week 12, rats in the CA-JV group had higher right ventricular systolic pressure (RVSP), medial area/total area (MA/TA) and percentage of fibrous tissue (F%) than those in the Control group. These changes were associated with up-regulation of MMP-1,9 mRNA and increased expression of MMP-1,9 proteins. Pretreatment with simvastatin decreased the shunt-induced RVSP, MA/TA and F% in pulmonary arteries. In addition, lung MMP-1,9 mRNA and proteins levels decreased toward normal levels in simvastatin-treated rats.

CONCLUSIONS:

Simvastatin ameliorated the structural and functional derangements of pulmonary arterioles caused by the CA-JV shunt, partly associated with the suppression of up-regulated MMP-1, as well as MMP-9. Simvastatin may play a role in the treatment of systemic-pulmonary shunt-induced PAH diseases, such as congenital heart disease.

• Authors: Jianping Yao, Mai Xiong, Bing Tang, Guangxian Chen, Mengya Liang, Xiaofan Ma, Zhiping Wang, Zhongkai Wu
• Journal: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery (Eur J Cardiothorac Surg) Vol. 42 Issue 5 Pg. e121-7 (Nov 2012) ISSN: 1873-734X [Electronic] Germany
• PMID: 23087098 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Simvastatin
• Matrix Metalloproteinase 9
• Mmp9 protein, rat
• MMP1 protein, rat
• Matrix Metalloproteinase 1

Topics

• Animals
• Arteriovenous Shunt, Surgical
• Biomarkers (metabolism)
• Blood Pressure (drug effects)
• Blotting, Western
• Carotid Arteries (surgery)
• Disease Models, Animal
• Down-Regulation
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology, therapeutic use)
• Hypertension, Pulmonary (drug therapy, metabolism, pathology, physiopathology)
• Jugular Veins (surgery)
• Male
• Matrix Metalloproteinase 1 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Pulmonary Artery (drug effects, metabolism, pathology, physiology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Simvastatin (pharmacology, therapeutic use)
• Treatment Outcome