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Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N‐oxide‐generating pathway, modulates platelet responsiveness and thrombosis risk
Author(s): ,
W. Zhu
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
J. A. Buffa
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
Z. Wang
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
M. Warrier
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
R. Schugar
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
D. M. Shih
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
N. Gupta
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
J. C. Gregory
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
E. Org
Affiliations:
Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA
,
X. Fu
Affiliations:
Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA
,
L. Li
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
J. A. DiDonato
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
A. J. Lusis
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA
,
J. M. Brown
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA. Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA
S. L. Hazen
Affiliations:
Lerner Research Institute, Cleveland Clinic, Cleveland, USA. Heart and Vascular Institute, Cleveland Clinic, Cleveland, USA
Correspondence: Stanley L. Hazen, Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NC‐10, Cleveland, OH 44195, USA|Tel.: +1 216 445 9763|E‐mail: hazens@ccf.org
ISTH Academy. L. Hazen S. Sep 4, 2018; 230958
Stanley L. Hazen
Stanley  L. Hazen

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Background
Gut microbes play a critical role in the production of trimethylamine N‐oxide (TMAO), an atherogenic metabolite that impacts platelet responsiveness and thrombosis potential. Involving both microbe and host enzymatic machinery, TMAO generation utilizes a metaorganismal pathway, beginning with ingestion of trimethylamine (TMA)‐containing dietary nutrients such as choline, phosphatidylcholine and carnitine, which are abundant in a Western diet. Gut microbial TMA lyases use these nutrients as substrates to produce TMA, which upon delivery to the liver via the portal circulation, is converted into TMAO by host hepatic flavin monooxygenases (FMOs). Gut microbial production of TMA is rate limiting in the metaorganismal TMAO pathway because hepatic FMO activity is typically in excess.
Objectives
FMO3 is the major FMO responsible for host generation of TMAO; however, a role for FMO3 in altering platelet responsiveness and thrombosis potential in vivo has not yet been explored.
Methods
The impact of FMO3 suppression (antisense oligonucleotide‐targeting) and overexpression (as transgene) on plasma TMAO levels, platelet responsiveness and thrombosis potential was examined using a murine FeCl‐induced carotid artery injury model. Cecal microbial composition was examined using 16S analyses.
Results
Modulation of FMO3 directly impacts systemic TMAO levels, platelet responsiveness and rate of thrombus formation in vivo. Microbial composition analyses reveal taxa whose proportions are associated with both plasma TMAO levels and in vivo thrombosis potential.
Conclusions
The present studies demonstrate that host hepatic FMO3, the terminal step in the metaorganismal TMAO pathway, participates in diet‐dependent and gut microbiota‐dependent changes in both platelet responsiveness and thrombosis potential in vivo.
Keyword(s)
blood platelets, cardiovascular disease, choline, gut microbe, thrombosis
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