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A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors

Cell. 2020-03; 
Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, Cajka T, Mohan ML, Li L, Wu Y, Funabashi M, Ramer-Tait AE, Naga Prasad SV, Fiehn O, Rey FE, Tang WHW, Fischbach MA, DiDonato JA, Hazen SL.
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ORF cDNA Clones/MolecularCloud Mammalian expression plasmids for transfection were made from the human ADRA2A, ADRA2B, and ADRB2 cDNA sequences which were synthesized by Genscript (Piscataway, NJ) to lack their initiating methionine (ATG) but to include an amino terminal encoded GGS linker and these ORFs were cloned in-frame behind the DYK (FLAG) epitope in pcDNA3.1(+)-N-DYK to create pcDNA3.1(+)-ADRA2A-N-DYK, pcDNA3.1(+)-ADRA2B-N-DYK and pcDNA3.1(+)-ADRB2-N-DYK respectively Get A Quote

摘要

Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary ph... More

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