Project: Project 3: Role of macrophage Piezo1 in atherosclerosis
About
Atherosclerosis (AS) is a metabolic and inflammatory disease of the large arteries 58-61. Coronary artery disease is the most common type of heart disease caused by AS, that accounts for about 50% of all deaths in the Western society 62. The main causes for disease development include elevated cholesterol level, high blood pressure, smoking, diabetes, obesity and a lack of physical activity 59. AS is a major public health issue worldwide, leading to significant morbidity, mortality, and economic burden 62.
Macrophages centrally contribute to the initiation and progression of plaque formation within the arteries 63-66.Initially, circulating monocytes adhere to the endothelium upon inflammatory activation because of the expression of various adhesion molecules 67. Subsequently, differentiated macrophages within the arterial wall ingest oxLDL particles and transform into foam cells, which are lipid-laden cells that contribute to plaque formation 65,68-70. Macrophages also secrete various pro-inflammatory cytokines and chemokines (eg, IL-1, TNF-α, MCP-1) that contribute to the inflammatory response, characteristic of AS 60,61. Released pro-inflammatory cytokines further attract immune cells, thus perpetuating a vicious cycle of inflammation and plaque growth. In addition, macrophages release metalloproteinases (MMPs) that degrade the extracellular matrix, destabilizing the plaques and ultimately making it prone to rupture 66,71. Macrophages in advanced plaques can undergo apoptosis or necrosis 72. The resulting necrotic core will further contribute to plaque instability, increasing the risk of rupture. Ruptured plaques expose the underlying pro-thrombotic material to the bloodstream, inducing the formation of a thrombus that can occlude the arterial lumen causing myocardial infarction or stroke 58,59,73. Conversely, macrophages can play a protective role in AS by promoting cholesterol efflux to high-density lipoprotein (HDL) particles 74. Moreover, certain macrophage subsets (such as M2 polarized macrophages) can adopt an anti-inflammatory phenotype that will contribute to resolve inflammation and promote tissue repair 75. Thus, macrophages can exert a dual role in the progression and/or potential regression of atherosclerotic lesions.
The hemodynamic forces exerted by blood flow, including shear stress, tensile stress, and cyclic strain on the arterial walls have also long been recognized to play a significant role in the initiation of AS 76-79. Areas of arteries exposed to disturbed shear stress, such as arterial curvatures and branch points are more prone to AS 79-82. In contrast, regions with high, unidirectional steady shear stress tend to be protected from plaque formation. The mechanobiology of endothelial cells has been the subject of intense research over the years and its role in AS is now well established 76-79. However, the role of macrophage mechanotransduction and its possible implication in AS is only starting to emerge 83.
We are currently exploring the functional role of Piezo1 in monocytes and macrophages during AS development. This approach provides the basis for a rigorous pipeline that can be adapted to address additional issues related to inflammation, innate immunity and other metabolic disorders.