Abstract
Introduction: Age-related gut microbiota alteration may underpin vascular disease. Yet, little is known about the role of cardiovascular disease-linked gut microbial metabolite phenylacetyl glutamine (PAG) in vascular aging. Hypothesis: 1) PAG promotes endothelial senescence via epigenetic and SASP modulation; 2) Acetate rescues PAG-induced endothelial senescence and impaired angiogenesis. Methods: We quantitated plasma concentrations of PAG and its precursor phenylacetic acid (PAA) in old and young healthy humans (>65 vs. 18-35 years, n=41-45) and mice (24 vs. 3 months, n=6) by LC-MS/MS. Fecal acetate was measured by HPLC-RI. We then treated proliferating human aortic endothelial cells (PEC) with PAA+Glutamine (for PAG production) to examine its effects on cellular senescence, epigenetic and SASP state, mitochondrial respiration, and angiogenesis. Results: We showed markedly higher plasma PAA and PAG concentrations in old humans and mice vs. young ones. Yet, fecal acetate level was significantly lower in old vs. young mice. PAG significantly induced senescence (increased SA-β-gal positive cells and transcripts p16, p19, p21) and mitochondrial ROS production in PEC associated with upregulated SASP (IL1α, IL1β, TNF-α and adhesion molecule VCAM-1), and reduced mitochondrial respiration. PAG markedly reduced angiogenesis (endothelial sprouting and tube formation) accompanied by decreases in CaMKKβ T286 and histone deacetylase 4 (HDAC4 S632 ) phosphorylation, histone 3 (H3) acetylation, and the subsequent Mef2A-mediated eNOS S1177 phosphorylation. By contrast, acetate (3 μM) rescued senescence and impaired angiogenesis and mitochondrial function and reversed SASP and epigenetic alteration induced by PAG in PEC. Conclusions: We conclude that acetate regulates the aging gut microbial metabolite PAG-induced SASP and epigenetic alteration, by which rescues endothelial senescence and represents a potential vascular regenerative strategy.
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