Effects of Antisense Oligonucleotides against C-Reactive Protein on the Development of Atherosclerosis in WHHL Rabbits

Qi Yu,Enqi Liu,Sijun Dong,Ahmed Bilal Waqar,Mark J Graham,Rosanne M Crooke,Jianglin Fan,Xianghong Yang,Masashi Shiomi,Bo Ning,Zhengcao Liu

doi:10.1155/2014/979132

Abstract

Increased plasma levels of C-reactive protein (CRP) are closely associated with cardiovascular diseases, but whether CRP is directly involved in the pathogenesis of atherosclerosis is still under debate. Many controversial and contradictory results using transgenic mice and rabbits have been published but it is also unclear whether CRP lowering can be used for the treatment of atherosclerosis. In the current study, we examined the effects of the rabbit CRP antisense oligonucleotides (ASO) on the development of atherosclerosis in WHHL rabbits. CRP ASO treatment led to a significant reduction of plasma CRP levels; however, both aortic and coronary atherosclerotic lesions were not significantly changed compared to those of control WHHL rabbits. These results suggest that inhibition of plasma CRP does not affect the development of atherosclerosis in WHHL rabbits.

Highlights

C-reactive protein (CRP) is a classical plasma protein marker that is markedly elevated in the acute phase of inflammation, infection, and tissue damage and has been broadly used for monitoring and differential diagnosis [1, 2]
Ample data from both clinical and experimental studies have shown that a high level of plasma CRP is a risk factor as well as marker for cardiovascular diseases [5,6,7,8,9], some studies failed to prove the risk of CRP compared to other risk factors
We found that Watanabe heritable hyperlipidemic (WHHL) rabbits are an excellent model for the study of CRP and its relationship with atherosclerosis because they have higher levels of plasma CRP and immunoreactive CRP proteins are present in lesions of atherosclerosis [24]

Summary

Introduction

C-reactive protein (CRP) is a classical plasma protein marker that is markedly elevated in the acute phase of inflammation, infection, and tissue damage and has been broadly used for monitoring and differential diagnosis [1, 2]. CRP is mainly expressed by hepatocytes, and its synthesis is regulated at the posttranscriptional level by cytokines [4]. Ample data from both clinical and experimental studies have shown that a high level of plasma CRP is a risk factor as well as marker for cardiovascular diseases [5,6,7,8,9], some studies failed to prove the risk of CRP compared to other risk factors. The JUPITER trial (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) showed that a lipid-lowering drug, rosuvastatin (Crestor), can significantly reduce the incidence of major cardiovascular events, even in apparently healthy subjects not exhibiting established risk factors such as hyperlipidemia, but with elevated high-sensitive CRP levels [10].

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Results

Conclusion