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
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Anmerkungen
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The journal of clinical investigation. - 132, 9 (2022) , e152373, ISSN: 1558-8238
- Ereignis
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Veröffentlichung
- (wo)
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Freiburg
- (wer)
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Universität
- (wann)
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2022
- Urheber
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Morrell, Craig N
Mix, Doran
Aggarwal, Anu
Bhandari, Rohan
Godwin, Matthew
Owens, Phillip
Lyden, Sean P.
Doyle, Adam
Krauel, Krystin
Rondina, Matthew T.
Mohan, Amy
Lowenstein, Charles J.
Shim, Sharon
Stauffer, Shaun
Josyula, Vara Prasad
Ture, Sara K.
Yule, David I.
Wagner, Larry E.
Ashton, John M.
Elbadawi, Ayman
Cameron, Scott J.
- DOI
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10.1172/JCI152373
- URN
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urn:nbn:de:bsz:25-freidok-2277502
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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25.03.2025, 13:51 MEZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- Morrell, Craig N
- Mix, Doran
- Aggarwal, Anu
- Bhandari, Rohan
- Godwin, Matthew
- Owens, Phillip
- Lyden, Sean P.
- Doyle, Adam
- Krauel, Krystin
- Rondina, Matthew T.
- Mohan, Amy
- Lowenstein, Charles J.
- Shim, Sharon
- Stauffer, Shaun
- Josyula, Vara Prasad
- Ture, Sara K.
- Yule, David I.
- Wagner, Larry E.
- Ashton, John M.
- Elbadawi, Ayman
- Cameron, Scott J.
- Universität
Entstanden
- 2022
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