Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms
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
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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Research Article Vascular biology

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

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 6

A OR2L13 agonist potently inhibits platelet aggregation.

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A OR2L13 agonist potently inhibits platelet aggregation. (A) Platelets w...
(A) Platelets were isolated from healthy individuals and preincubated with (–) carvone or (+) carvone (300 μM) for 30 minutes. Platelets were stimulated with ADP (0.1 μM), and light transmission aggregometry was performed to assess platelet activation. Representative tracings for each agonist are shown. (B) Carvone (300 μM) or forskolin (10 μM) incubation individually or together for 30 minutes followed by platelet stimulation with ADP (0.1 μM). Light transmission aggregometry was performed to assess platelet activation. Representative aggregometry tracings are shown. V, vehicle; C, (–) carvone, f, forskolin. n = 3. Differences between groups were assessed by 1-way ANOVA followed by Bonferroni’s correction; *P < 0.0001, **P = 0.0003, and ***P < 0.0001 versus vehicle. (C) Summary data from light transmission aggregometry for each agonist are presented as the mean ± SEM. n = 3. *P = 0.08 versus vehicle and **P = 0.0013 versus vehicle, by 1-way ANOVA followed by Bonferroni’s correction. (D) Platelets were isolated from healthy individuals and preincubated with (–) carvone (0–500 μM) for 30 minutes, followed by stimulation with ADP (0.1 μM). Light transmission aggregometry was performed to assess platelet activation. Representative tracings for each agonist are shown. (E) Summary data for each concentration of (–) carvone are presented as the mean ± SEM in the presence of ADP stimulation (0.1 μM). The downward red arrow is ADP in the presence of vehicle to which all data points were compared. n = 3 in each group. *P < 0.05 versus vehicle, by 1-way ANOVA followed by Bonferroni’s correction. The broken blue line indicates the log IC50 concentration of (–) carvone.