AQP1 differentially orchestrates endothelial cell senescence.

1. Redox Biol. 2024 Oct;76:103317. doi: 10.1016/j.redox.2024.103317. Epub 2024 Aug 22. AQP1 differentially orchestrates endothelial cell senescence. Shabanian K(1), Shabanian T(1), Karsai G(2), Pontiggia L(3), Paneni F(1), Ruschitzka F(1), Beer JH(4), Saeedi Saravi SS(5). Author information: (1)Center for Translational and Experimental Cardiology, Department of Cardiology, University Hospital Zurich, University of Zurich, 8952, Schlieren, Switzerland; University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland. (2)Institute of Clinical Chemistry, University Hospital Zurich, 8952, Schlieren, Switzerland. (3)Tissue Biology Research Unit, University Children's Hospital Zurich, 8952, Schlieren, Switzerland; Children's Research Center, University Children's Hospital Zurich, 8032, Zurich, Switzerland; Faculty of Medicine, University of Zurich, 8032, Zurich, Switzerland. (4)Center for Molecular Cardiology, University of Zurich, 8952, Schlieren, Switzerland; Department of Internal Medicine, Cantonal Hospital Baden, 5404, Baden, Switzerland. Electronic address: hansjuerg.beer@ksb.ch. (5)Center for Translational and Experimental Cardiology, Department of Cardiology, University Hospital Zurich, University of Zurich, 8952, Schlieren, Switzerland; University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland. Electronic address: soheil.saeedi@uzh.ch. 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, 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. Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.redox.2024.103317 PMCID: PMC11388013 PMID: 39180980 [Indexed for MEDLINE] Conflict of interest statement: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Soheil Saeedi reports was provided by University of Zurich. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.