Citrullination is the post-translational conversion of peptidyl-arginine to peptidyl-citrulline and is mediated by a family of enzymes known as peptidyl-arginine deiminases (PADs). Citrullination has been demonstrated to be an inflammation-dependent process due to the constitutive expression of the enzymes PAD2 and PAD4 by polymorphonuclear leukocytes as well as cells of the monocytes/macrophage lineage. The link between inflammation and atherosclerosis is well established with numerous mechanisms implicated including oxidative modification of protective HDL proteins induced by the enzyme myeloperoxidase. However, another post- translation modification recently identified within the atherosclerotic plaque is protein citrullination. We have identified several citrullinated plaque proteins including prominently, the HDL-associated protein ApoA-I . ApoA-I facilitates removal of excess cellular cholesterol thus impeding atherogenesis. Additionally, ApoA-I has been demonstrated to have direct anti-inflammatory effects thus limiting vascular inflammation. We propose to study citrullination as a novel mediator of inflammation induced atherosclerotic progression. This work represents a scientific progression of our previous studies demonstrating citrullination within the atherosclerotic plaque. The proposed studies will provide new insights into how a group of enzymes ubiquitously carried by white blood cells, peptidyl arginine-deiminases (PADs), contributes to the effect of pathologic inflammation within the atherosclerotic plaque. The main goal of this application is to investigate the role of ApoA-I citrullination as a risk factor for atherosclerotic development and progression. Specifically, we propose to: 1. Define the sites of ApoA-I citrullination from in-vitro citrullinated ApoA-I as wellas ApoA-I isolated from human plasma, and from within the atherosclerotic plaque; 2. Confirm and characterize citrullination-dependent abrogation of ApoA-I cholesterol efflux capacity and to identify residues critical for mediating this abrogation; 3. Use pharmacologic and genetic animal models to define the role of citrullination in atherosclerosis progression, and 4. Quantitate citrullination of plasma ApoA-I and correlate with subclinical atherosclerosis as well as atherosclerotic events. Success of these studies could identify novel mechanisms contributing to inflammation-driven atherosclerosis and have the potential to both contribute to the development of diagnostic tests for cardiovascular risk prediction, as well as identifying potentia therapeutic targets for the treatment and/or prevention of coronary artery disease.
Cardiovascular disease is the leading cause of death in the developed world. The proposed studies will investigate whether modification of apolipoprotein A1 by a process known as citrullination results in decreased ability to remove bad cholesterol from the blood vessels of the heart thus contributing to the progression of atherosclerosis and resultant cardiovascular disease. Success of these studies could not only identify those at increased risk of cardiovascular disease, but these could also lead to the development of novel therapies to treat or prevent atherosclerotic heart disease.
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