This free paper is good. It relates to why arteries get thrombosis and how iron accumulation causes the endothelial cells to become old. Not an easy paper and it goes deeper than is important to us Prana investors. However it opens us to understand how some day PBT434 could be used in preventing vascular thrombosis, a bigger indication area what there is now for statins. I think Dr. Sinclair likes this paper because he has published similar type of papers. IMO this paper is very important for an iron chelator as PBT434.iScience. 2018 Dec 11;11:205-223. doi: 10.1016/j.isci.2018.12.005. [Epub ahead of print]Neuropilin-1 Controls Endothelial Homeostasis by Regulating Mitochondrial Function and Iron-Dependent Oxidative Stress.
Issitt T1, Bosseboeuf E1, De Winter N1, Dufton N1, Gestri G2, Senatore V3, Chikh A4, Randi AM1, Raimondi C5.Abstract
The transmembrane protein neuropilin-1 (NRP1) promotes vascular endothelial growth factor (VEGF) and extracellular matrix signaling in endothelial cells (ECs). Although it is established that NRP1 is essential for angiogenesis, little is known about its role in EC homeostasis. Here, we report that NRP1 promotes mitochondrial function in ECs by preventing iron accumulation and iron-induced oxidative stress through a VEGF-independent mechanism in non-angiogenic ECs. Furthermore, NRP1-deficient ECs have reduced growth and show the hallmarks of cellular senescence. We show that a subcellular pool of NRP1 localizes in mitochondria and interacts with the mitochondrial transporter ATP-binding cassette B8 (ABCB8). NRP1 loss reduces ABCB8 levels, resulting in iron accumulation, iron-induced mitochondrial superoxide production, and iron-dependent EC senescence. Treatment of NRP1-deficient ECs with the mitochondria-targeted antioxidant compound mitoTEMPO or with the iron chelator deferoxamine restores mitochondrial activity, inhibits superoxide production, and protects from cellular senescence. This finding identifies an unexpected role of NRP1 in EC homeostasis.
