Biology subjects

Beer, J. H.

Publications and source records attributed to Beer, J. H..

2 recordsLinked to original sources

bioRxiv2024

AQP1 Differentially Orchestrates Endothelial Cell Senescence

Accumulation of senescent endothelial cells (ECs) with age is a pivotal driver of cardiovascular diseases in aging. However, little is known about the mechanisms and signaling pathways that regulate EC senescence. In this report, we delineate a previously unrecognized role of aquaporin 1 (AQP1) in orchestrating extracellular hydrogen peroxide (H2O2)-induced cellular senescence in aortic ECs. Our findings underscore AQP1s differential impact on senescence hallmarks, including cell-cycle arrest, senescence-associated secretory phenotype (SASP), and DNA damage responses, intricately regulating angiogenesis. In proliferating ECs, AQP1 is crucial for maintaining angiogenic capacity, whereas disruption of AQP1 induces morphological and mitochondrial alterations, culminating in senescence and impaired angiogenesis. Conversely, Aqp1 knockdown or selective blockade of AQP1 in senescent ECs rescues the excess H2O2-induced cellular senescence phenotype and metabolic dysfunction, thereby ameliorating intrinsic angiogenic incompetence. Mechanistically, AQP1 facilitates H2O2 transmembrane transport, exacerbating oxidant-sensitive kinases CaMKII-AMPK. This process suppresses HDAC4 translocation, consequently de-repressing Mef2A-eNOS signaling in proliferating ECs. However, in senescent ECs, AQP1 overexpression is linked to preserved HDAC4-Mef2A complex and downregulation of eNOS signaling. Together, our studies identify AQP1 as a novel epigenetic regulator of HDAC4-Mef2A-dependent EC senescence and angiogenic potential, highlighting its potential as a therapeutic target for antagonizing age-related cardiovascular diseases. Highlights* AQP1 is upregulated in aortic endothelial cells with aging * AQP1 differentially orchestrates H2O2-mediated EC senescence * AQP1 plays a dual role in regulating angiogenesis in proliferating and senescent ECs * AQP1 controls EC function by differentially modulating HDAC4-Mef2A pathway * AQP1 deficiency restores angiogenic capacity in senescent ECs

molecular biology↗

bioRxiv2023

Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging

Endothelial cell (EC) senescence plays a crucial role in the development of cardiovascular diseases in aging population. Gut microbiota alterations are emerging as significant factors present in cellular senescence associated with aging. However, little is known about how aging-related changes in gut microbiota are causally implicated in EC senescence. Here we show that gut microbiota-dependent phenylacetic acid (PAA) and its derivative, phenylacetylglutamine (PAGln), are elevated in a human aging cohort (TwinsUK, n=7,303) and in aged mice. Metagenomic analyses revealed a marked increase in the abundance of PAA-producing microbial pathways (PPFOR and VOR), which were positively associated with the abundance of Clostridium sp. ASF356, higher circulating PAA concentrations, and endothelial dysfunction in old mice. We found that PAA potently induces EC senescence and attenuates angiogenesis. Mechanistically, PAA increases mitochondrial H2O2 generation, which aggravates IL6-mediated HDAC4 translocation and thereby upregulates VCAM1. In contrast, exogenous acetate, which was reduced in old mice, rescues the PAA-induced EC senescence and restores angiogenic capacity through markedly alleviating the SASP and epigenetic alteration. Our studies provide direct evidence of PAA-mediated crosstalk between aging gut microbiota and EC senescence and suggest a microbiota-based therapy for promoting healthy aging. HighlightsO_LIAging-related gut microbiota alterations contribute to a marked elevation of plasma PAA and PAGln in humans and mice C_LIO_LIClostridium sp. ASF356 contributes to PPFOR-mediated PAA formation in aged mice C_LIO_LIGut-derived PAA promotes endothelial senescence and impairs angiogenesis C_LIO_LIPAA induces mitochondrial H2O2 generation, by which drives epigenetic alterations and SASP in ECs C_LIO_LIAcetate rescues PAA-induced EC senescence and mitochondrial dysfunction C_LIO_LIAcetate improves angiogenesis by reducing HDAC4 phosphorylation and SASP C_LI

cell biology↗