Epigenetic Regulation of F2RL3 Associates With Myocardial Infarction and Platelet Function
DNA hypomethylation at the (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. encodes protease-activated receptor 4, a potent thrombin recep...
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Published in | Circulation research Vol. 130; no. 3; pp. 384 - 400 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Lippincott Williams & Wilkins
04.02.2022
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Subjects | |
Online Access | Get full text |
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Summary: | DNA hypomethylation at the
(F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown.
encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease.
We conducted multiple independent experiments to assess whether DNA hypomethylation at
in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at
, and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at
(N=41). We used an in vitro model to explore the biological response of
to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact
gene expression.
Observationally, DNA methylation at
mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at
and a corresponding 1.7-(95% CI, 1.2-2.4,
=0.04) fold increase in
mRNA. Results from reporter assays suggest the exon 2 region of
may help control gene expression.
Smoking-induced epigenetic DNA hypomethylation at
appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies
DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk but from any feature potentially influencing
regulation in a similar manner. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0009-7330 1524-4571 |
DOI: | 10.1161/CIRCRESAHA.121.318836 |