Poster Presentation HUPO 2019 - 18th Human Proteome Organization World Congress

The Impact of Asialylated Glycoproteins in Coronary Artery Disease. (#793)

Benjamin J Pullen 1 2 3 , Achini K Vidanapathirana 1 2 3 , Jarrad M Goyne 1 2 3 , Stephen J Nicholls 2 4 , Nicolle H Packer 2 5 , Christina A Bursill 1 2 3
  1. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
  2. Australian Research Council (ARC) Centre of Excellence for Nanoscale BioPhotonics (CNBP) , Adelaide, South Australia, Australia
  3. Vascular Research Centre, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
  4. MonashHeart, Monash University, Clayton, Victoria, Australia
  5. Department of Biomolecular Design and Discovery Centre, Macquarie University, Sydney, New South Wales, Australia

Coronary artery disease (CAD) is the build-up of fatty plaque within the walls of the blood vessels within the heart, resulting in reduced blood flow to the heart tissue. Macrophages are cells that are key to the build of fatty atherosclerotic plaque. A recent landmark study has revealed that the presence of a rare loss-of-function mutation in a glycoprotein receptor, ASGR1, significantly correlates with a reduction (34%, p=4.0×10−6) in the risk of CAD. The dramatic reduction in CAD risk could not be explained purely by the reduction in plasma cholesterol levels, suggesting that other mechanisms are involved. This project aims to determine whether: 1) ASGR1 is expressed in macrophages, 2) expression changes with macrophage polarity and 3) ASGR1 plays a role in important macrophage functions.

Bone marrow cells weredifferentiated from monocyte-like cells to bone marrow-derived macrophages (BMDMs) over seven days. BMDMs were also polarised to either an ‘M1-like’ inflammatory or ‘M2-like’ anti-inflammatory macrophage phenotype. Samples were collected throughout the differentiation and polarisation process for analysis of mRNA using quantitative PCR and protein using Western blotting. We found that ASGR1 is expressed in macrophages at both the mRNA and protein level. ASGR1 expression increases with differentiation from a monocyte to a macrophage. There were no changes in ASGR1 levels between the M1 and M2-like phenotype.

We have demonstrated, for the first time, the presence of ASGR-1 in BMDMs, highlighting a possible new role for ASGR1 in atherosclerosis. Future studies will compare changes in the function and glycoprotein profile of BMDMs from ASGR1-/-and wildtype mice ex vivo. These studies will determine if ASGR1 represents a new therapeutic target for the prevention of CAD.