Altered endothelial biology
Endothelial cell behaviour is particularly driven by the blood flow pattern to which it is exposed. This is the basis for the focal development of atherosclerosis, which predominantly develops at branch points in arteries, where the endothelium is exposed to disturbed blood flow.
In contrast, plaque erosion most frequently occurs on stenotic plaques in areas of elevated flow. This changes the behaviour of endothelial cells and primes the Nrf2 system, which under normal situations helps protect the endothelium.
Smoking is a known risk factor for plaque erosion. We have shown that smoking hyperactivates the Nrf2 system, upregulating the expression of OSGIN1+2 and promoting endothelial detachment. We also have initial leads on compounds that might inhibit plaque erosion.
Elevated flow and smoking can trigger endothelial detachment. Computational fluid dynamic (CFD) assessment of eroded plaques in patients identified that plaque erosion frequently occurs proximal to, or within, the point of maximum stenosis, exposing the endothelium to elevated flow.
Elevated flow modifies endothelial phenotype, which on exposure to soluble factors from cigarette smoke and the inflammatory cytokine TNFα highly activate the transcription factor Nrf2 and the expression of OSGIN1 and 2. This induces detachment of human coronary artery endothelial cells, which can be rescued by inhibition of HSP70 and AMPK activation.
Academic papers
-
Satta, S, Mahmoud, AM, Wilkinson, FL, Alexander, MY and White, SJ (2017) The Role of Nrf2 in Cardiovascular Function and Disease, Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 9237263, 18 pages
-
Satta, S, et al A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques
-
McElroy, M, Kim, Y, Niccoli, G et al(2021) Identification of the haemodynamic environment permissive for plaque erosion. Sci Rep, 11,7253