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
Taraneh Shabanian
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
Gergely Karsai
Institute of Clinical Chemistry, University Hospital Zurich, 8952, Schlieren, Switzerland
Luca Pontiggia
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
Francesco Paneni
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
Frank Ruschitzka
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
Jürg H. Beer
Center for Molecular Cardiology, University of Zurich, 8952, Schlieren, Switzerland; Department of Internal Medicine, Cantonal Hospital Baden, 5404, Baden, Switzerland; Corresponding author. Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
Seyed Soheil Saeedi Saravi
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; Corresponding author. Center for Translational and Experimental Cardiology, University Hospital Zurich, University of Zurich, Wagistrasse 12, 8952, Schlieren, Switzerland.
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.
