Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.03.13.584782

AQP1 Differentially Orchestrates Endothelial Cell Senescence

Shabanian, K.·Shabanian, T.·Karsai, G.·Lettlova, S.·Pontiggia, L.·Ruschitzka, F.·Beer, J. H.·Saeedi Saravi, S. S.
View original source ↗Export metadata ↓

Abstract

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

Source connections

Explore related subjects

molecular biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Shabanian, K., Shabanian, T., Karsai, G., Lettlova, S., Pontiggia, L., Ruschitzka, F., Beer, J. H., Saeedi Saravi, S. S.. 2024-03-14. AQP1 Differentially Orchestrates Endothelial Cell Senescence. https://doi.org/10.1101/2024.03.13.584782

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Engineered Miniature ParTasR Enables Efficient PAMless Genome Editing

TIGR-Tas system holds great promise for genome-engineering applications owing to its compact size and PAMless targeting capability. However, its low editing efficiency in mammalian cells severely limits its broader utility. Here, we engineered a highly active variant of ParTasR, termed eTasR, through structure-guided rational design of ParTasR combined with fusion to the exonuclease TREX2. eTasR increased mammalian editing efficiency from the original 4.29% to 48.94% with an average 26.52-fold increase, significantly surpassing the efficiency of SpRY, a reported version of PAM-free nuclease. More importantly, single-AAV delivery enabled efficient Hpd disruption in vivo, resulting in robust phenotypic rescue. Thus, eTasR provides a compact, PAMless and highly efficient platform for genome editing and therapeutic applications.

molecular biology↗
bioRxiv2026

Enhancing pancreatic islet cell survival via NMDAR antagonist-driven ROR1 activation as revealed by phosphoproteomics

NMDA receptors (NMDARs) control function and survival not only of neurons, but also of insulin-producing pancreatic beta cells. Since insufficient insulin secretion and beta cell death are key events during diabetes development, targeting NMDARs offers a therapeutic approach. Specifically, the NMDAR antagonist dextrorphan (DXO) increases glucose-stimulated insulin secretion in clinical trials. Furthermore, treatment with DXO or optimized DXO derivatives prevents pancreatic islet cell death upon diabetogenic insults. Nonetheless, the signaling pathways induced by NMDAR inhibition are poorly understood. Here, we use complementary approaches, phosphoproteomics and tyrosine kinase profiling, to demonstrate that DXO and its derivatives rapidly regulate multiple intracellular signaling clusters, including mTOR and ERK signaling, in pancreatic islets. Notably, mTOR inhibition, but not ERK inhibition, is sufficient to negate DXO's protective effects. Further, we show that activation of Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) is a universal event upon NMDAR inhibition in islets. Simultaneous knockdown of Ror1/ROR1 and its paralogue Ror2/ROR2 compromises the viability of both mouse and human islets, highlighting the ROR1/2 signaling axis as a promising avenue for enhancing beta cell survival.

molecular biology↗
bioRxiv2026

An ssRNA Phage Single-gene Lysis Protein Targeting MraY Reveals Convergent Evolution Across the RNA-DNA Phage Boundary

Small lytic phages of the ssRNA Leviviricetes and ssDNA Microviricetes achieve host lysis by expression of a single protein, designated as an Sgl protein. Four ssRNA Sgls have been shown to inhibit steps in peptidoglycan biosynthesis: three target MurJ, the Lipid II flippase, and one targets MurA, the committed step of the pathway. A fifth Sgl, the E protein of the canonical ssDNA microvirus {varphi}X174, inhibits MraY, which catalyzes the synthesis of the first lipid-linked intermediate. This inhibition requires SlyD, a cytoplasmic FKBP-type peptidyl-prolyl cis-trans isomerase. The Sgl of the Caulobacter ssRNA phage {varphi}Cb5 (Cebevirus halophobicum) has not been characterized. Here, we present physiological evidence that Sgl{varphi}Cb5 targets MraY. Moreover, we show that, despite the absence of detectable sequence similarity, Sgl{varphi}Cb5 shares several features with the {varphi}X174 E protein, including the distribution of hydrophobic and charged residues, a proposed N-out, C-in membrane topology, and retention of lytic activity in an Sgl{varphi}Cb5 -LacZ fusion. Furthermore, expression of the Caulobacter cytoplasmic FKBP-type peptidyl-prolyl cis-trans isomerase CC2799 enhances Sgl{varphi}Cb5 -mediated lysis in E. coli. These parallels between Sgl function in a DNA phage and an RNA phage either represent remarkably consonant convergent evolution or some evolutionary cross-over event for which there is currently no precedent.

molecular biology↗