Search for new therapeutic options to prevent and treat plaque neovascularization and atherogenesis

Atherosclerosis, the most common cause of cardiovascular diseases (CVD), is characterized by progressive inflammation and accumulation of lipids in the arterial vessel wall starting early in life. When the disease reaches an advanced stage, one of the detrimental factors triggering acute end-point events such as myocardial infarction and stroke, is the formation of new blood vessels within the plaque. These vessels are formed through a complex orchestrated growth known as angiogenesis. In this thesis we aimed at, on one hand, stabilizing the atherosclerotic plaque by targeting intraplaque angiogenesis, and on the other, reducing atherosclerosis by the use of natural compounds. Key players in the process of angiogenesis are endothelial cells, and recently, endothelial cell metabolism has gained attention in being the target in treating pathological angiogenesis. Among, it is PFKFB3 protein which is a key regulatory enzyme of the glycolytic pathway. A variety of inhibitors of this important target have been studied, and a plethora of biological effects related to the process of angiogenesis have been reported. The most well studied one is small molecule 3PO. However, since recent studies have disputed its mechanism of action, we sought at defining the thermodynamic profile of the 3PO-PFKFB3 interaction. To this end, we revealed that the biological effects leading to reduced angiogenesis upon 3PO use were PFKFB3-independent as there is no biomolecular interaction between these two components. In order to reiterate the role of PFKFB3 in angiogenesis, we made use of a bona fide PFKFB3 inhibitor, compound AZ67. This allowed us to demonstrate that pharmacological inhibition of PFKFB3 enzyme leads to reduced angiogenesis in vitro and in vivo, making this a worthwhile target to investigate, not only from a therapeutic perspective in atherosclerosis, but also in oncology and other angiogenesis-related disorders. On the other hand, the new approaches in targeting atherosclerosis development by use of natural compounds like chalcones (belonging to calorie-restriction group) showed beneficial effects. The use of 4,4’-dimethoxychalcone (possessing a wide range of health benefits) resulted in reduced atherosclerotic plaque formation in an in vivo model of atherosclerosis. Other in vivo, and in vitro parameters were also altered in favor of atheroprotection. These observations reveal an additional beneficial property of DMC, which, as a natural compound can be regarded for further therapeutic possibilities in treating atherosclerotic cardiovascular disease.

ISBN:978-94-6416-954-6

Jaar van publicatie:2022

Trefwoorden:Doctoral thesis

Toegankelijkheid:Closed