Novel aspects of atherosclerosis : focusing on new target genes and the effect of cholesterol-lowering

Atherosclerosis is most often the main underlying cause of cardiovascular diseases (CVDs), accounting for more than 31% of all deaths worldwide. It is driven by the uptake of low-density lipoproteins (LDL) by a dysfunctional arterial endothelium. It involves a complex interplay of genetic and cellular factors that result in an uncontrolled inflammatory response which can potentially be fatal. The main treatment for atherosclerosis is cholesterol-lowering drugs, statins. Despite their use, clinical events still occur. In this thesis, three papers regarding CVDs and some of the key events happening during atherosclerosis are discussed.

In paper I the role of Lim domain-binding 2 (Ldb2) as a master regulator of transendothelial migration of leukocytes (TEML) during atherosclerosis was investigated. We described its function as a modulator of the leukocyte extravasation process using in vivo mouse models and in vitro systems. By examining Ldb2-deficient mice we found increased atherosclerotic lesions and decreased plaque stability. Their TEML activity was increased, especially regarding monocytes and macrophages, the principal initiators of the atherosclerotic process. Additionally, the role of this gene was reinforced by a functional SNP found in coronary artery disease (CAD) cohorts associated with increased risk of myocardial infarction (MI).

In the following publication, paper II, we describe the function of the newly identified cholesterol-responsive gene Poliovirus receptor-related 2 (PVRL2) in atherosclerosis. This gene, as a member of the nectin family, plays a major role during TEML in the extravasation step. Regarding atherosclerosis development, Pvrl2-deficient mice showed fewer lesions and more stable plaques. An increased endothelial expression of Pvrl2 coincided with an increase in leukocyte gene expression, strengthening its potential role during TEML. In fact, we found a significant decrease in leukocyte migration in the Pvrl2-deficient mice using in vivo assays. Moreover, we observed its endothelial expression and cholesterol-responsiveness in humans.

The effect of cholesterol-lowering on atherosclerosis is well established, and statins remain the main treatment. Since statins are prescribed to most CVD patients due to the underlying atherosclerosis, their specific effect on single diseases are not well studied. In paper III we aimed to identify the effect of angiotensin II (AngII)-induced AAA on atherosclerosis and the influence of cholesterol-lowering on abdominal aortic aneurysm (AAA) in an atherosclerotic mouse model. We found a low incidence of AAA formation after AngII infusion, possibly because the levels of cholesterol in our mice were not high enough. Nevertheless, AngII was found to enhance atherosclerosis and leukocyte infiltration, stressing the importance of the renin-angiotensin system on atherosclerosis and suggesting a controlling effect of cholesterol in the model.

All three papers emphasize the importance of cholesterol during CVDs. Further research in order to elucidate the underlying mechanisms and detailed role of the identified gene targets could have a major impact on the development of new drugs. These could act directly on the TEML process, thus modulating the inflammatory response and attenuating disease complications.

List of scientific papers

I. Lim domain binding 2: a key driver of transendothelial migration of leukocytes and atherosclerosis. Ming-Mei Shang, Husain A. Talukdar, Jennifer J. Hofmann, Colin Niaudet, Hassan Foroughi Asl, Rajeev K. Jain, Aranzazu Rossignoli, Cecilia Cedergren, Angela Silveira, Bruna Gigante, Karin Leander, Ulf de Faire, Anders Hamsten, Arno Ruusalepp, Olle Melander, Torbjörn Ivert, Tom Michoel, Eric E. Schadt, Christer Betsholtz, Josefin Skogsberg, Johan L.M. Björkegren. Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;34:2068-2077.
https://doi.org/10.1161/ATVBAHA.113.302709

II. Poliovirus Receptor-Related 2: A Cholesterol-Responsive Gene Affecting Atherosclerosis Development by Modulating Leukocyte Migration. Aránzazu Rossignoli, Ming-Mei Shang, Hanna Gladh, Christine Moessinger, Hassan Foroughi Asl, Husain Ahammad Talukdar, Oscar Franzén, Steffen Mueller, Johan L.M. Björkegren, Erika Folestad, Josefin Skogsberg. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:534-542.
https://doi.org/10.1161/ATVBAHA.116.308715

III. Plasma Cholesterol Lowering in an AngII-infused Atherosclerotic Mouse Model with Moderate Hypercholesterolemia. Aránzazu Rossignoli, Emina Vorkapic, Anders Wanhainen, Toste Länne, Josefin Skogberg, Erika Folestad, Dick Wågsäter. [Submitted]