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Potential Targets for Imaging Atherosclerosis
Published in Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer, Cardiovascular Molecular Imaging, 2007
David N. Smith, Mehran M. Sadeghi, Jeffrey R. Bender
Atherogenesis can begin early in life with EC activation (2). The pathological process is initiated by lipid deposition seen early in the subendothelial space with resultant inflammatory cell infiltration. In the presence of high circulating levels, LDL cholesterol is taken up by the endothelium. Passing through caveoli, LDL becomes trapped in the subendothelial extracellular space (3). This impairs the secretion of vasodilatory and anti-inflammatory factors, such as NO (4). The altered endothelium releases endothelin-1 (ET-1) and angiotensin II (ATII), which function as vasoconstrictors. This leads to VSMC hypertrophy and vascular remodeling (5,6). Circulating monocytes expressing type A scavenger receptors, which recognize acetylated LDL molecules, transmigrate through the endothelium to engulf the lipids within the subendothelial space. Monocytes differentiate into activated macrophages expressing higher levels of SR-A (7), CD 32 (8), SR-BI (9), CD68 (10), and the better-characterized CD36. CD36 activates the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma, a cell differentiating transcription factor. While PPAR-gamma is involved in induction of genes related to lipid metabolism, it also promotes the differentiation of monocytes to macrophages and foam cells upon oxidized LDL (oxLDL) exposure (11,12). Oxidized LDL is formed by active oxidases [e.g., metalloproteinases, xanthine and NAD(P)H oxidases] in the intimal layer from macrophages and EC (13). The intracellular accumulation of cholesterol overwhelms the mitochondrial metabolic capacity and endoplasmic reticulum membrane integrity leading to organelle dysfunction, cell activation and release of proinflammatory cytokines and proteases within the growing lesion. Excess reactive oxygen species generated by the metabolism of lipids are incompletely neutralized by natural antioxidants (e.g., NADPH) (14,15), leading to further EC damage.
Cerebral perfusion and its association with serum endothelin-1 in multiple sclerosis
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Azza Bayoumi Hammad, Eman Mohammed Seif El Din, Ghada Saed Abdel Azim, Mohamed Ali Abboud
An increased production of the potent vasoconstrictive agent endothelin-1 (ET-1) by reactive astrocytes in focal demyelinated lesions appears to play an important role in reducing CBF in patients with MS. Endothelin A (ETA) receptor activation on vascular smooth muscle cells by ET-1 induces a dose-dependent vasoconstriction of human cerebral arteries, which can be antagonized by the ET-1 receptor antagonist, bosentan [5]. However, in an extension of their study, the authors found no increase in CBF in NAWM of the centrum semiovale of RRMS patients treated for 28 days with the ET-1 antagonist bosentan. In addition, they found that CBF in the centrum semiovale NAWM in the RRMS population (27 RRMS patients) was not different from that of healthy controls who were investigated with the same cerebral MRI protocol, software and scanner. But they did not measure the level of ET-1 in blood or CSF [6].