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Decrypting the pleiotropic role of the immune checkpoint molecule, ICOS-Ligand, in immunoconversion of pro-inflammatory to pro-senescence endothelial cell phenotype in cardiovascular diseases
Dr. Max Wacker, Prof. Dr. med. Jens Wippermann, Prof. Dr. Fred Schaper, Dr. Anna Dittrich
    1. State-of the Art and Key Research Question(s): Coronary Artery Disease (CAD) pathophysiology is initiated when coronary arteries supplying blood to the heart are being blocked with the accumulating plaques, forming varying degree of fatty streaks, built from inflammatory cells, including monocytes derived macrophages and lymphocytes [3-5]. These blood patrolling immune cells attain an inflammatory state in response to the signals delivered by a dysfunctional endothelium, which is initially caused by deposition and subsequent physicochemical modification of circulating low-density lipoproteins (LDL) in subendothelial spaces. Further, the oxidized lipid ladened pathological macrophages residing at subendothelial spaces produce excessive reactive oxygen species (ROS) and proinflammatory cytokines, including IL-6, which decreases nitric oxide bioavailability and substantially increases oxidative stress in the plaque microenvironment. Under these circumstances, the damaged endothelium releases VWF, which is not only best known for its role in hemostasis and thrombosis, supporting platelet adhesion and aggregation, but also plays a central role in vascular inflammation, favoring leukocyte recruitment and extravasation. Such a constant stimulus, including oxidative stress, initiates endothelial senescence, the process characterized by cell cycle arrest and changes in pro-inflammatory gene expression, in the vasculature. With regard to vascular inflammation in CAD patients, we consider a shift from pro-inflammatory to the pro - senescence state of a vascular endothelium as a key decision point that must be focused and targeted to mitigate the conversion of senescence. This is highly essential because senescence associated with vascular endothelium secretes senescence associated secretory phenotypes (SASP), in addition to many dramatic changes occurring at the intracellular level. Further, endothelial-SASP aggravates and sustain chronic inflammation throughout the lifetime of a CAD patient, which lowers the quality of autologous vessel when used for coronary artery bypass graft (CABG) surgery, as CABG still is considered as a gold standard method for multivessel coronary artery disease. These autologous bypass grafts (vessels) are highly prone to getting occluded with thrombus and therefore exhibit a poor long-term potency, which evidently raises the question on the quality of autologous vessel. Of note, vascular endothelial senescence was evident in arterial diseases. Apart, it has been reported that the ligand for inducible costimulator (ICOS-L) were increasingly expressed on an activated endothelium, under the influence of proinflammatory cytokines. The ICOS-L is one of the immune checkpoint molecule that binds to ICOS, expressed on activated T cells, where the ICOS-L/ICOS axis exhibits multifaceted role in immune function, including polarization towards (i) TH1 immunity; (ii) TH2 immunity; (iii) TH17 immunity; (iv) Tregs immunity; (v) germinal center formation and B cell immunity in antibody production. However, the potential role of ICOS-L in inducing or preventing endothelial senescence is not yet explored and is therefore largely unknown.

1.2 Unresolved key questions: Since cardiovascular inflammation diseases remains to be the first leading cause of death globally, we intend to stamp on critical window phase where the transformation of vascular endothelium occurs from pro-inflammatory to pro-senescence state, with the aim of preserving the quality of vessels, thereby avoiding further worsening from chronic inflammation due to senescence and thereby to subsequently increase the patency rate when used for CABG surgery. For this purpose, we explore an in-depth role of ICOS-L/ICOS axis in this above-mentioned decision phase in the presence of atherosclerotic progressive factors.
A. The atherosclerosis related soluble factors, including vWF, blood clotting factors and immune cell associated cytokines, IL-6, IL-1ß, IL-8 increase the endothelial transmembrane expression level of ICOS-L will be explored
B. Despite increased ICOS-L expression, the knowledge of its functional significance on vascular endothelium is largely unknown and will therefore be addressed during the state of (i) initial inflammation, (ii) progressive inflammation and (iii) transformation of inflammation to senescence. This will be achieved by determining the recruitment of intracellular anti-senescence molecules, including SIRTUIN-1 and FOXO1, where these pathways will be thoroughly investigated. Here, we intend to employ the ApoE-/-atherosclerotic mouse model, ICOS-L transgenic and knockout mouse to investigate the senomorphic role of ICOS-L in vivo as well as in vitro, with endothelial cell culture systems, with ICOS-L overexpression and ICOS-L knockout using CRIPSR-Cas9 tools.

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