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Article
Nabil Alkayed
Oregon Health & Science University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3489-4730
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Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We identified G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor antagonistically regulated by two endogenous eicosanoids: 15-HETE, which stimulates GPR39 to increase mVSMC intracellular calcium and augment microvascular CVR, and 14,15-EET, which inhibits these actions. Furthermore, zinc ion acts as an allosteric modulator of GPR39 to potentiate the efficacy of the two ligands. Finally, GPR39 knockout mice are protected from myocardial ischemia compared to wild-type littermates. Our findings will have a major impact on understanding the roles of eicosanoids in cardiovascular physiology and disease, and provide an opportunity for the development of novel GPR39-targeting therapies for cardiovascular disease.
One Sentence Summary: GPR39 is a microvascular smooth muscle cell receptor regulated by two vasoactive eicosanoids with opposing actions.
Keywords
GPR39, coronary vascular resistance, eicosanoids
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Yes there is potential Competing Interest. This research involves technology of which N. Alkayed, S. Kaul, and S. Nagarajan are co-inventors and which has been licensed, in part by OHSU, to Vasocardea. OHSU and S. Kaul have a financial interest in Vasocardea, a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by OHSU
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Article
Nabil Alkayed
Oregon Health & Science University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3489-4730
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 02 Jun, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We identified G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor antagonistically regulated by two endogenous eicosanoids: 15-HETE, which stimulates GPR39 to increase mVSMC intracellular calcium and augment microvascular CVR, and 14,15-EET, which inhibits these actions. Furthermore, zinc ion acts as an allosteric modulator of GPR39 to potentiate the efficacy of the two ligands. Finally, GPR39 knockout mice are protected from myocardial ischemia compared to wild-type littermates. Our findings will have a major impact on understanding the roles of eicosanoids in cardiovascular physiology and disease, and provide an opportunity for the development of novel GPR39-targeting therapies for cardiovascular disease.
One Sentence Summary: GPR39 is a microvascular smooth muscle cell receptor regulated by two vasoactive eicosanoids with opposing actions.
Figure 1
Figure 2
Figure 3
Figure 4
Yes there is potential Competing Interest. This research involves technology of which N. Alkayed, S. Kaul, and S. Nagarajan are co-inventors and which has been licensed, in part by OHSU, to Vasocardea. OHSU and S. Kaul have a financial interest in Vasocardea, a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by OHSU
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementalFigures.pdf
Supplemental Figures
- SupplementaryMaterialFinal.docx
Supplementary Information
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