The Function And Mechanism Of CKIP-1 In The Regulation Of Atherosclerosis

Cardiovascular diseases are the leading cause of mortality worldwide.Atherosclerosis is the most common and important cardiovascular disease.Today we understand that atherosclerosis is a chornic inflammatory disease characterized by the accumulation of lipids and fibrous elements in the large arteries.Over time,these lesions,which are known as atherosclerotic plaques,mature and gain new characteristics.The most severe clinical events follow the rupture of a plaque,which exposes the prothrombotic material in the plaque to the blood and causes sudden thrombotic occlusion of the artery at the site of disruption.In the heart,atherosclerosis can lead to myocardial infarction,unstable angina,heart failure and sudden cardiac death.Aside from addressing unmet medical needs at the public health policy and clinical care levels,a deep and nuanced understanding of the underlying biological processes should enable development of safe and effective treatments.There is a growing understanding that macrophages play a very important role in the development of atherosclerosis.In atherosclerosis,the key initiating step is that the subendothelial accumulation of apolipoprotein B-containing lipoproteins leads to the recruitment of monocytes,the cells of the immune system that give rise to macrophages.Macrophages derived from these recruited monocytes ingest the accumulated normal and modified lipoproteins,which transform them into the cholesterol-laden foam cells,triggering a series of inflammatory response.Macrophage-derived foam cell formation is a critical early event in atherogenesis,with an incomplete understanding of the molecular pathways involved.Previous studies suggested that CKIP-1?casein kinase-2 interacting protein-1?played an important role in the regulation of cell proliferation and apoptosis.CKIP-1depletion in mice manifested an age-dependent accumulation in bone mass and those mice were also susceptible to pressure overload-induced pathological cardiac hypertrophy.However,the physiological role of CKIP-1 in atherosclerosis in vivo is unknown.In this study,we explored the function and molecular mechanism of CKIP-1 in the development of atherosclerosis in cultured cells,animal models and clinical cases.Our main conclusions are as follow:First,our results support a protective role of CKIP-1 in atherosclerosis in an ApoE^–/–?apolipoprotein E deficient?mouse model.We found that CKIP-1 was highly expressed in atherosclerotic lesions.We generated double gene knockout mice lacking CKIP-1 and ApoE and then age-and sex-matched ApoE^–/–CKIP-1^–/–and ApoE^–/–littermates were fed with a Western diet for 8 weeks.En face analysis of Oil Red O-stained atherosclerotic lesion area revealed an about 2.2-fold increase in ApoE^–/–CKIP-1^–/–mice when compared with ApoE^–/–mice.CKIP-1 deficiency promoted atherosclerosis without changing the plasma cholesterol and lipoprotein profiles.Furthermore,CKIP-1 deficiency significantly increased the total necrotic areas and promoted the degradation of collagen and thinning of fibrous cap,which were important features of vulnerable plaques,and promoted vascular inflammation.Second,increased atherosclerosis in ApoE^–/–CKIP-1^–/–mice is mediated by cells of hematopoietic origin.To define the effector cell that suppresses atherosclerosis in ApoE^–/–CKIP-1^–/–mice,bone marrow transplantation was carried out with lethally irradiated ApoE^–/–mice as recipients followed by reconstitution with bone marrow from ApoE^–/–or ApoE^–/–CKIP-1^–/–mice,respectively.We found ApoE^–/–mice that received ApoE^–/–CKIP-1^–/–bone marrow exhibited markedly increased lesion areas compared with mice transplanted with ApoE^–/–bone marrow.Thus,the effector cell is of hematopoietic origin.Third,CKIP-1 is a novel regulator of macrophage foam cell formation.Deletion of CKIP-1 promotes macrophage cholesterol accumulation and foam cell formation and increased lipoprotein uptake may contribute to enhanced foam cell formation in CKIP-1^–/–macrophages.Furthermore,deletion of CKIP-1 augments the cellular uptake of oxLDL,at least in part through up-regulation of LOX-1?lectin-like oxidized low-density lipoprotein receptor-1?via increase the transcriptional activity of PPAR??peroxisome proliferator-activated receptor??by HDAC4?histone deacetylase 4?.Therapeutic approaches that target macrophages to treat cardiovascular disease have not yet been realized,partly because the fundamental biology remains somewhat enigmatic.Here,we found that CKIP-1 plays a macrophage-dependent,anti-atherosclerotic role in the regulation of cholesterol metabolism and inflammatory response in a mouse model of atherosclerosis.Our study provides a new insight to macrophage function and regulation in atherosclerosis as well as the novel role of CKIP-1 in the development of cardiovascular disease.