Seyed Soheil Saeedi Saravi (Switzerland)
University of Zurich
Center for Molecular Cardiology
Dr. Seyed Soheil Saeedi Saravi, PharmD, PhD, senior scientist at University of Zurich and formerly at Harvard Medical School, received his PhD in 2016 from Tehran University of Medical Sciences (TUMS), followed by a post doc at Harvard Medical School. His research areas include cardiovascular aging, atherosclerosis, and redox biology. He has authored of over 55 peer-reviewed publications, edited 8 books and chapters, and presented at over 30 international conferences. He has served as editorial board and reviewer of >20 prestigious journals, e.g. European Heart Journal and Proceedings of National Academy of Sciences USA, and professional member of over 10 international scientific associations, including American Heart Association (AHA), European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). He has been honored with numerous international and national awards (25 prizes), namely, including "Paul Dudley White International Award" from American Heart Association, "AGLA Walter Riesen Award" from Swiss Atherosclerosis Association, "European Atherosclerosis Society Young Investigator Fellowship 2021", and "Harvard Postdoctoral Fellowship".

Presenter of 1 Presentation

 Conference Calendar

ACETATE REVERSES THE GUT MICROBIOTA METABOLITE PHENYLACETYL GLUTAMINE (PAG)-INDUCED ENDOTHELIAL SENESCENCE BY EPIGENETIC AND SASP MODULATION

Session Name
0640 - Endothelial cell biology in atherosclerosis (ID 6)
Session Type
Workshop - Pathogenesis, vascular biology
Date
Tue, 24.05.2022
Session Time
15:45 - 17:15
Room
Anitschkow - Silver Plenary hall
Presenter
Lecture Time
16:55 - 17:05

Abstract

Background and Aims

The gut microbiota metabolite PAG is clinically linked to CAD and arterial thrombosis. Yet, very little is known about the role and mechanisms of PAG in vascular cells. We sought to investigate 1) effects of PAG on metabolic/epigenetic state and senescence-associated secretory phenotype (SASP) in ECs; 2) reversal effects of acetate on PAG-induced endothelial senescence and dysfunction.

Methods

We examined the effects of PAG (100 μM; according to our preliminary studies) with or without acetate (500 μM) on cellular senescence (via SA-β-galactosidase staining) and function (via in vitro angiogenesis and migration assays), and epigenetic and SASP characterization (via biochemical assays) in proliferating human aortic EC (PEC; passage 5).

Results

We found that PAG increases mitochondrial ROS production accompanied by downregulated isocitrate dehydrogenase-2 (Idh2), a marker of mitochondrial function. PAG-treated cells revealed a significant reduction in angiogenesis and cell migration accompanied by decreased phosphorylation of eNOSS1177 and AMPKT172 and activation of acetyl-coA carboxylase (ACC) that leads to the loss of acetyl-coA, leading to decreased histone 3 (H3) acetylation (p<0.001, n=6). Importantly, PAG significantly induced senescence, as represented by increased SA-β-gal-positive cells (p<0.01), and upregulated SASP (TNF-α and VCAM-1; p<0.001). Conversely, acetate intriguingly increased phosphorylation of AMPKT172 and eNOSS1177 and H3 acetylation accompanied by reduced SA-β-gal-positive cells, downregulated SASP and improved mitochondrial function. Additionally, acetate restored angiogenesis and migration in PAG-treated cells to the magnitude seen in PEC.

figure 1.png

Conclusions

We conclude that PAG causes endothelial dysfunction via metabolic/epigenetic and SASP modulation and that acetate represent new possibilities for rejuvenating senescent ECs and preventing aging-related CVD.

Hide