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Sex-dependent Expression Of Neutrophil Gelatinase-associated Lipocalin In Aortic Valve Stenosis
Eva Jover1, Rafael Sabada1, Lara Matilla1, Mattie Garaikoetxea1, Amaya Fernández-Celis1, Alicia Gainza1, Frederic Jaisser2, Natalia López-Andrés1.
1Cardiovascular Translational Research. Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Pamplona, Spain, 22Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France.

OBJECTIVE: Aortic valve (AV) stenosis is the commonest form of adult valvular heart disease (VHD) and the valve interstitial cell (VIC) is pivotal to its pathogenesis. Neutrophil gelatinase-associated lipocalin (NGAL) is a pleiotropic glycoprotein that mainly signals towards 24p3R and contributes to several diseases. We aimed to study the role of NGAL in human AV stenosis.
METHODS: Surgical AV leftovers and serum samples were harvested from 126 patients (57.4% men), with no kidney disease, undergoing elective surgical valve replacement. VICs were challenged for 2, 4 and 8 days with hyperphosphate (2.6mM, HP) media ± rhNGAL, or NGAL-silenced for in vitro validation studies. Histology, immunohistochemistry, western blotting, ELISA and zymography were performed on AVs and VICs, as appropriate.
RESULTS: Circulating NGAL was associated with inflammation (Tumor Necrosis Factor-α and Interleukin (IL)-6) and oxidative stress (Myeloperoxidase (MPO) and 8OHdG) markers. NGAL was expressed by inflammatory infiltrates and VICs in AVs. Expression of tissue NGAL was correlated with inflammation (IL-6, RANTES and Galectin-3), oxidative stress (MPO, Endothelial Nitric Oxide Synthase, Malondialdehyde (MDA) and Carboxy Methyl Lysine (CML)). NGAL was greater expressed in AV from men than women (217.70 ± 23.41 vs. 119.5 ± 11.31, p=0.0098). In vitro, intracellular NGAL and 24p3R were strongly down-regulated whereas secreted NGAL was enhanced from day 4 (0.55±0.15, p=0.0283; 0.32±0.09 p=0.0000; 8.00±2.32, p=0.0053 fold changes, respectively), only in calcifying men-derived VICs (n=6). Such effects were overall prevented in women-derived VICs (n=5), unless NGAL was silenced. RhNGAL endowed calcifying VICs with increased necrosis (52KDa-PARP1), apoptosis (Caspase-3) and oxidative stress (CML, MDA, nitrotyrosine and pNF-κB) at day 8.
CONCLUSIONS: NGAL is associated with inflammation and oxidative stress in AV stenosis, and promotes pro-apoptotic and necrotic phenotypes in vitro only in men. NGAL signaling may drive sex-dependent mechanisms clinically relevant to the VHD.


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