Danger signaling pathways in aortic disease

Abstract

The aorta connects the heart to the peripheral circulation and organs. It is necessary for the regulation of hemodynamics and therefore, aortic disease affects all organs and the survival of the individual. In aortic valve stenosis, the thin and smooth cusps that make up the aortic valve become thickened, fibrous, and calcified, leading to valve stiffness and reduced cusp compliance. Aortic valve stenosis is associated with significant morbidity and mortality. Nevertheless, there is still a lack of a reliable marker to predict disease progression. Current treatments for aortic valve stenosis are surgical and invasive, therefore, there is a need for earlier indicators. The development and progression of aortic valve stenosis is caused by certain factors, for instance chronic inflammation and the accumulation of cholesterol. This study specifically focuses on investigating these two factors and shedding light on their pivotal role in the development of aortic valve stenosis, to gain a deeper understanding and potential avenues for intervention in the management of this condition. The first project addressing chronic inflammation is about cellular and biochemical pathways activated by the innate immune system. Essential components of the innate immune system are pattern recognition receptors, which recognize microbial molecular patterns as well as altered or mislocalized self-molecules. Pattern recognition receptors include a variety of receptors, such as the Toll-like receptor family. One part of this thesis provides an insight into the role of Toll-like receptor 3 in valve cells and mice. Activation of this receptor caused calcification and inflammation in cells and in the living organism, which could be blunted after Toll-like receptor 3 inhibition or knockdown. Thus, the findings not only support the endogenous role of Toll-like receptor 3 in the development of aortic valve stenosis, but also suggest that specific Toll-like receptor 3 inhibition may be beneficial for the treatment or prevention of aortic valve stenosis. The second part of this study moves on to describe the role of cholesterol crystals in the pathogenesis of aortic valve stenosis. Cholesterol crystal infiltration has been recognized as a contributing factor in the formation of atherosclerotic plaques and the initiation of inflammatory processes. Furthermore, it has been implicated in the onset of calcification. By investigating the role of cholesterol crystals, this study aims to shed light on their involvement in the underlying mechanisms of aortic valve stenosis, providing insights into the progression of the disease and potentially uncovering novel therapeutic strategies targeting cholesterol crystal-related pathways. This work could demonstrate the ability to solubilize these crystals with cyclodextrin. In this way, in vitro experiments could further demonstrate a higher calcification pattern after the addition of cholesterol crystals, which in turn could be reduced by solubilizing the crystals with cyclodextrin.