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Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms
Craig N. Morrell, … , Ayman Elbadawi, Scott J. Cameron
Craig N. Morrell, … , Ayman Elbadawi, Scott J. Cameron
Published March 24, 2022
Citation Information: J Clin Invest. 2022;132(9):e152373. https://doi.org/10.1172/JCI152373.
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Research Article Vascular biology

Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms

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Abstract

As blood transitions from steady laminar flow (S-flow) in healthy arteries to disturbed flow (D-flow) in aneurysmal arteries, platelets are subjected to external forces. Biomechanical platelet activation is incompletely understood and is a potential mechanism behind antiplatelet medication resistance. Although it has been demonstrated that antiplatelet drugs suppress the growth of abdominal aortic aneurysms (AAA) in patients, we found that a certain degree of platelet reactivity persisted in spite of aspirin therapy, urging us to consider additional antiplatelet therapeutic targets. Transcriptomic profiling of platelets from patients with AAA revealed upregulation of a signal transduction pathway common to olfactory receptors, and this was explored as a mediator of AAA progression. Healthy platelets subjected to D-flow ex vivo, platelets from patients with AAA, and platelets in murine models of AAA demonstrated increased membrane olfactory receptor 2L13 (OR2L13) expression. A drug screen identified a molecule activating platelet OR2L13, which limited both biochemical and biomechanical platelet activation as well as AAA growth. This observation was further supported by selective deletion of the OR2L13 ortholog in a murine model of AAA that accelerated aortic aneurysm growth and rupture. These studies revealed that olfactory receptors regulate platelet activation in AAA and aneurysmal progression through platelet-derived mediators of aortic remodeling.

Authors

Craig N. Morrell, Doran Mix, Anu Aggarwal, Rohan Bhandari, Matthew Godwin, Phillip Owens III, Sean P. Lyden, Adam Doyle, Krystin Krauel, Matthew T. Rondina, Amy Mohan, Charles J. Lowenstein, Sharon Shim, Shaun Stauffer, Vara Prasad Josyula, Sara K. Ture, David I. Yule, Larry E. Wagner III, John M. Ashton, Ayman Elbadawi, Scott J. Cameron

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Figure 4

Characterization of OR2L13 agonists.

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Characterization of OR2L13 agonists.
(A) Human OR2L13 was subcloned in f...
(A) Human OR2L13 was subcloned in frame with HA (GFP in a secondary cassette, green) and coexpressed with receptor transport protein 1s (RTP1s) (mCherry in a secondary cassette, red) stably in HEK293/cAMP cells. Microscopy and Western blotting confirmed OR2L13-HA expression. Original magnification, ×20. TCL, total cell lysate. OR2L13 ligands stimulated (Golf), and adenyl cyclase produced cAMP. (B) A cAMP response element (CRE) expressing HEK293 cells with stable integration of OR2L13-HA was utilized to screen for ligands. (C) Alpha screen of olfactory ligands in OR2L13 transduced/nontransduced cells with more than 1.0 ratio (red dashed line) for OR2L13 activation; (–) carvone activated OR2L13 to generate cAMP (performed in duplicate, horizontal line indicates the mean). Results of a confirmatory experiment with vehicle versus (–) carvone are shown as the mean ± SEM. n = 4 (right). *P = 0.079, **P = 0.0001, and ***P < 0.0001 versus vehicle, by 1-way ANOVA followed by Bonferroni’s correction.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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