Abstract 10509: Aquaporin 1 Differentially Controls Endothelial Cell Senescence by Epigenetic and SASP Modulation

Abstract

Introduction: Aquaporin 1 (AQP1) has been implicated in oxidant sensing, but little is known about its differential role in metabolism and function of proliferating (PEC) and senescent (SEC) endothelial cells. We sought to investigate 1) role of AQP1 in modulation of epigenetic modification and senescence-associated secretory phenotype (SASP) in PEC and SEC, and 2) reversal effects of Aqp1 deletion/inhibition on endothelial senescence and dysfunction. Methods: We executed Aqp1 deletion or selective blockade of AQP1 pore (with Bacopaside II 10 μM) to inhibit H 2 O 2 transport in human aortic endothelial cells (PEC p.5 vs SEC p.15 ) and examined its effects on cellular senescence (via SA-β-galactosidase staining) and function (via in vitro angiogenesis and migration assays), and H 2 O 2 -modulated epigenetic modification and SASP (via biochemical assays). Results: We found that AQP1 facilitates physiological H 2 O 2 supply which is necessary for angiogenesis and cell migration in PEC accompanied by marked increase in AMPK T172 phosphorylation and inhibition of acetyl-coA carboxylase (ACC) that provides acetyl-coA for an increased histone 3 (H3) acetylation. Importantly, Aqp1 deletion/inhibition significantly induced senescence and mitochondrial dysfunction in PEC associated with increased SA-β-gal positive cells, upregulated SASP (TNF-α and ICAM-1), and downregulated Idh2. By contrast, decreased AMPK T172 phosphorylation and H3 acetylation accompanied by increased SA-β-gal positive cells, upregulated SASP and mitochondrial dysfunction seen in SEC were reversed by Aqp1 deletion/inhibition. In SEC, we have shown that Aqp1 deletion restores angiogenesis and migration comparable to PEC. Conclusion: We conclude that AQP1 differentially controls metabolism and function in young and senescent ECs via epigenetic and SASP modulation and that AQP1 inhibition represent new possibilities for rejuvenating senescent ECs and treating cardiovascular disease.