Acetate reverses the gut microbiota metabolite phenylacetyl glutamine (PAG)-induced endothelial senescence by epigenetic and SASP modulation

Saravi, SS Saeedi; Karsai, G.; Lee, P.; Beer, J.H.

doi:10.1016/j.atherosclerosis.2022.06.060

Cited by 1 publication

(12 citation statements)

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“…Moreover, oxidized HDAC4 has been shown to interact more easily with protein kinases of the CaMKII family. Consistently, our prior investigation demonstrated that gut-derived phenylacetic acid, by NOX4-mediated H 2 O 2 generation, both oxidizes and phosphorylates (through CaMKII stimulation) HDAC4, facilitating its cytosolic accumulation in PECs [22]. We next observed that HDAC4 nuclear export facilitates de-repression of Mef2A in PECs.…”

Section: Discussionsupporting

confidence: 84%

“…It returns to the fact that redox/metabolic status in ECs orchestrates permanent changes in their epigenetic programming [2]. The CaMKII-mediated hierarchical phosphorylation of HDAC4 S632 facilitates its subcellular localization [22]. In accordance to our and others' previous studies, H 2 O 2 regulates HDAC4 shuttle between cell cytosol and nucleus through two potential mechanisms, one direct oxidation of HDAC4, and another one H 2 O 2 -regulated phosphorylation of HDAC4 in ECs [22,32].…”

Section: Discussionsupporting

confidence: 79%

“…EC senescence is intricately characterized by profound epigenetic alterations, particularly histone modifications, contributing to dynamic comprehensive changes of gene expression profiles that orchestrate the progression of vascular aging [22,30]. HDAC4 is a key regulator of histone modifications and subsequent expression of the genes involved in senescenceassociated phenotypes in endothelial cells [22,31]. Our and others studies suggest that posttranslational modification of HDAC4 may modulate histone acetylation states, impacting gene expression patterns associated with endothelial cell senescence and impaired angiogenesis [22,32].…”

Section: Aqp1-regulated Ec Senescence Is Mediated By Hdac4-mef2a Pathwaymentioning

confidence: 68%

Section: Aqp1-regulated Ec Senescence Is Mediated By Hdac4-mef2a Pathwaymentioning

confidence: 99%

“…1D,E, cellular senescence, as a hallmark of aging, is associated with significant AQP1 upregulation in SECs as opposed to PECs. AQP1 has been recognized to transport H 2 O 2 in specific cell types [13], which may promote premature cellular senescence [21,22]. To prove the role of AQP1 in regulation of H 2 O 2mediated EC senescence, we transduced PECs (control) with ultrasensitive H 2 O 2 biosensor, AV5-HyPer7.2-NES, and detected H 2 O 2 levels in the cell cytosol which was markedly reduced following siAQP1 transfection or treatment with a clinically approved AQP1 inhibitor, Bacopaside II, in the presence of exogenous H 2 O 2 (50 μM; Fig.…”

Section: Aging Leads To Upregulation Of Aqp1 In Endothelial Cells In ...mentioning

confidence: 99%

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AQP1 Differentially Orchestrates Endothelial Cell Senescence

Shabanian,

Karsai

et al. 2024

Preprint

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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 AQP1’s 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,Aqp1knockdown 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 H2O2transmembrane 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

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 79%

Section: Aqp1-regulated Ec Senescence Is Mediated By Hdac4-mef2a Pathwaymentioning

confidence: 68%

Section: Aqp1-regulated Ec Senescence Is Mediated By Hdac4-mef2a Pathwaymentioning

confidence: 99%

Section: Aging Leads To Upregulation Of Aqp1 In Endothelial Cells In ...mentioning

confidence: 99%

See 3 more Smart Citations

AQP1 Differentially Orchestrates Endothelial Cell Senescence

Shabanian,

Karsai

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Acetate reverses the gut microbiota metabolite phenylacetyl glutamine (PAG)-induced endothelial senescence by epigenetic and SASP modulation

Cited by 1 publication

References 0 publications

AQP1 Differentially Orchestrates Endothelial Cell Senescence

AQP1 Differentially Orchestrates Endothelial Cell Senescence

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