AUTHOR=Omar Mohamed , Alexiou Maria , Rekhi Umar R. , Lehmann Konrad , Bhardwaj Aneesh , Delyea Cole , Elahi Shokrollah , Febbraio Maria 

TITLE=DNA methylation changes underlie the long-term association between periodontitis and atherosclerotic cardiovascular disease

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 10 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1164499

DOI=10.3389/fcvm.2023.1164499

ISSN=2297-055X

ABSTRACT=Periodontitis, the leading cause of adult tooth loss, has been identified as an independent risk factor for cardiovascular disease (CVD). Studies suggest that periodontitis, like other CVD risk factors, shows persistence of increased CVD risk even after mitigation. We hypothesized that periodontitis induces epigenetic changes in hematopoietic stem cells in the bone marrow (BM), and such changes persist after clinical elimination of the disease and underlie the increased CVD risk. To simulate clinical elimination of periodontitis and persistence of the hypothesized epigenetic reprogramming, we used a BM transplant approach. Using the low density lipoprotein receptor knockout (LDLRo) atherosclerosis mouse model, BM donor mice were fed a high fat diet to induce atherosclerosis, and orally inoculated with Porphyromonas gingivalis (Pg), a keystone periodontal pathogen; a second group was sham inoculated. Naïve LDLRo mice were irradiated and transplanted with BM from one of the 2 donor groups. Recipients of BM from Pg-inoculated donors developed significantly more atherosclerosis, accompanied by cytokine/chemokines that suggested BM progenitor cell mobilization and were associated with atherosclerosis and/or PD. Using whole genome bisulfite sequencing, 375 differentially methylated regions (DMR) and global hypomethylation in recipients of BM from Pg-inoculated donors were observed. Some DMRs pointed to involvement of enzymes with major roles in DNA methylation and demethylation. In validation assays, we found a significant increase in activity of Ten-Eleven Translocase-2 and a decrease in activity of DNA methyltransferases. Plasma S-adenosylhomocysteine levels were significantly higher and the S-adenosylmethionine to S-adenosylhomocysteine ratio was decreased, both of which have been associated with CVD. These changes may be related to increased oxidative stress as a result of Pg infection. These data suggest a novel and paradigm shifting mechanism in the long term association between periodontitis and atherosclerotic CVD.