Rosiglitazone modulates collagen deposition and metabolism in atherosclerotic plaques of fat-fed ApoE-knockout mice.

Mingxue Zhou,Hongxu Liu,Hao Xu,Weihong Liu

doi:10.3892/etm.2015.2711

Abstract

Abnormal collagen deposition, as well as collagen metabolism, plays a crucial role in the formation and progression of vulnerable atherosclerotic plaques (VAPs), which are susceptible to rupture. According to our previous findings, rosiglitazone, a thiazolidinedione, can promote the stability of atherosclerotic plaques in fat-fed ApoE-knockout mice; however, it is unknown whether it can modulate collagen deposition and metabolism in VAPs. The present study was designed to determine the effect of rosiglitazone on collagen deposition and metabolism in the plaques of fat-fed ApoE-knockout mice. Following 13 weeks of the high-fat diet, the mice were randomized into three groups (10 mice/group) and intragastrically administered rosiglitazone, simvastatin and distilled water, respectively, for a further 13 weeks. The category of the collagen present in the plaques was evaluated using the picro-Sirius red polarization method. Additionally, the protein expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the plaques was determined using immunohistochemistry. The results showed that rosiglitazone reduced the lipid to collagen and type III to type I collagen ratios in the plaques, and these reductions were correlated with the reduction in the plaque MMP-9 to TIMP-1 ratio. These results suggest that rosiglitazone can modulate collagen deposition and metabolism and promote the stabilization of VAPs.

Highlights

Arterial diseases associated with atherosclerosis are the leading cause of morbidity and mortality worldwide
Our previous study showed that rosiglitazone could promote the stability of atherosclerotic plaques in fat‐fed ApoE‐knockout mice by reducing the vulnerability index, as well as the average quantity of buried fibrous caps, which may have been associated with its anti‐inflammatory effects [14]; the effect of rosiglitazone on collagen deposition and metabolism in atherosclerotic plaque was unclear
The present study indicated that rosiglitazone could modulate collagen deposition and metabolism in the atherosclerotic plaques of fat‐fed ApoE‐knockout mice, which may represent an important mechanism underlying the rosiglitazone‐induced stability of atherosclerotic plaques

Summary

Introduction

Arterial diseases associated with atherosclerosis are the leading cause of morbidity and mortality worldwide. Collagen is the main component of the extracellular matrix (ECM) in atherosclerotic plaques. It is a simple supporting structure and exerts numerous bioactivities, such as storing lipids, secreting cellular factors and promoting smooth muscle cell proliferation [5,6,7], and is associated with the progression of atherosclerosis [8]. The loss of collagen can result in structural weakness and reduces the resistance to the mechanical stresses associated with systole [9] The consequence of this structural weakness is plaque rupture, which is the key event in the initiation of coronary thrombosis and, ACSs, such as unstable angina and myocardial infarction [10]. In vulnerable atherosclerotic plaques (VAPs), types I and III collagen are the most evident collagen categories, and the former is the most important collagen to endure the loading in the plaque fibrous cap

Methods

Results

Conclusion