Sex-dependent expression of neutrophil gelatinase-associated lipocalin in aortic stenosis.
Aortic stenosis
Calcification
NGAL
Sex
Valve interstitial cells
Valvular heart disease
Journal
Biology of sex differences
ISSN: 2042-6410
Titre abrégé: Biol Sex Differ
Pays: England
ID NLM: 101548963
Informations de publication
Date de publication:
12 12 2022
12 12 2022
Historique:
received:
30
06
2022
accepted:
20
11
2022
entrez:
12
12
2022
pubmed:
13
12
2022
medline:
15
12
2022
Statut:
epublish
Résumé
Accumulating evidence suggest the existence of sex-related differences in the pathogenesis of aortic stenosis (AS) with inflammation, oxidative stress, fibrosis and calcification being over-represented in men. Neutrophil gelatinase-associated lipocalin (NGAL) is expressed in a myriad of tissues and cell types, and it is associated with acute and chronic pathological processes comprising inflammation, fibrosis or calcification. Sex-dependent signatures have been evidenced for NGAL which expression has been associated predominantly in males to metabolic and cardiovascular disorders. We aimed to analyse sex-related differences of NGAL in AS and its role in the inflammatory and fibrocalcific progression of AS. 220 (60.45% men) patients with severe AS elective for surgical aortic valve (AV) replacement were recruited. Immunohistochemistry revealed higher expression of NGAL in calcific areas of AVs and that was validated by qPCR in in 65 (60% men) donors. Valve interstitial cells (VICs) were a source of NGAL in these samples. Proteome profiler analyses evidenced higher expression of NGAL in men compared to women, and that was further validated by ELISA. NGAL expression in the AV was correlated with inflammation, oxidative stress, and osteogenic markers, as well as calcium score. The expression of NGAL, both intracellular and secreted (sNGAL), was significantly deregulated only in calcifying male-derived VICs. Depletion of intracellular NGAL in calcifying male-derived VICs was associated with pro-inflammatory profiles, dysbalanced matrix remodelling and pro-osteogenic profiles. Conversely, exogenous NGAL mediated inflammatory and dysbalanced matrix remodelling in calcifying VICs, and all that was prevented by the pharmacological blockade of NGAL. Owing to the over-expression of NGAL, the AV from men may be endowed with higher expression of inflammatory, oxidative stress, matrix remodelling and osteogenic markers supporting the progression of calcific AS phenotypes. The expression of NGAL in the VIC emerges as a potential therapeutic checkpoint, with its effects being potentially reverted by the pharmacological blockade of extracellular NGAL.
Sections du résumé
BACKGROUND
Accumulating evidence suggest the existence of sex-related differences in the pathogenesis of aortic stenosis (AS) with inflammation, oxidative stress, fibrosis and calcification being over-represented in men. Neutrophil gelatinase-associated lipocalin (NGAL) is expressed in a myriad of tissues and cell types, and it is associated with acute and chronic pathological processes comprising inflammation, fibrosis or calcification. Sex-dependent signatures have been evidenced for NGAL which expression has been associated predominantly in males to metabolic and cardiovascular disorders. We aimed to analyse sex-related differences of NGAL in AS and its role in the inflammatory and fibrocalcific progression of AS.
METHODS AND RESULTS
220 (60.45% men) patients with severe AS elective for surgical aortic valve (AV) replacement were recruited. Immunohistochemistry revealed higher expression of NGAL in calcific areas of AVs and that was validated by qPCR in in 65 (60% men) donors. Valve interstitial cells (VICs) were a source of NGAL in these samples. Proteome profiler analyses evidenced higher expression of NGAL in men compared to women, and that was further validated by ELISA. NGAL expression in the AV was correlated with inflammation, oxidative stress, and osteogenic markers, as well as calcium score. The expression of NGAL, both intracellular and secreted (sNGAL), was significantly deregulated only in calcifying male-derived VICs. Depletion of intracellular NGAL in calcifying male-derived VICs was associated with pro-inflammatory profiles, dysbalanced matrix remodelling and pro-osteogenic profiles. Conversely, exogenous NGAL mediated inflammatory and dysbalanced matrix remodelling in calcifying VICs, and all that was prevented by the pharmacological blockade of NGAL.
CONCLUSIONS
Owing to the over-expression of NGAL, the AV from men may be endowed with higher expression of inflammatory, oxidative stress, matrix remodelling and osteogenic markers supporting the progression of calcific AS phenotypes. The expression of NGAL in the VIC emerges as a potential therapeutic checkpoint, with its effects being potentially reverted by the pharmacological blockade of extracellular NGAL.
Identifiants
pubmed: 36510294
doi: 10.1186/s13293-022-00480-w
pii: 10.1186/s13293-022-00480-w
pmc: PMC9743642
doi:
Substances chimiques
Lipocalin-2
0
LCN2 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
71Subventions
Organisme : Instituto de Salud Carlos III
ID : CP13/00221
Organisme : Instituto de Salud Carlos III
ID : CD19/00251
Organisme : Instituto de Salud Carlos III
ID : FI19/00302
Organisme : Universidad de La Laguna
ID : ULL-MS-P14
Informations de copyright
© 2022. The Author(s).
Références
Front Cardiovasc Med. 2022 Feb 24;9:818371
pubmed: 35282345
Pediatr Res. 2011 Feb;69(2):112-7
pubmed: 21057377
J Thorac Cardiovasc Surg. 2012 Oct;144(4):830-7
pubmed: 22244555
Cancer Res. 2002 Aug 15;62(16):4540-4
pubmed: 12183401
Calcif Tissue Int. 1991 Sep;49(3):208-15
pubmed: 1933586
J Endocrinol. 1999 Jul;162(1):11-9
pubmed: 10396016
Circ Res. 2017 Feb 17;120(4):681-691
pubmed: 27879282
Gac Med Mex. 2016 Sep - Oct;152(5):612-617
pubmed: 27792695
Semin Cancer Biol. 2018 Apr;49:75-82
pubmed: 28546110
J Mol Cell Cardiol. 2018 Feb;115:32-38
pubmed: 29289651
Front Cardiovasc Med. 2019 Oct 29;6:156
pubmed: 31737648
J Cardiol. 2018 Mar;71(3):215-220
pubmed: 29258711
Thromb Haemost. 2007 Aug;98(2):427-33
pubmed: 17721627
J Am Coll Cardiol. 2019 May 7;73(17):2150-2162
pubmed: 31047003
J Clin Invest. 2010 Nov;120(11):4065-76
pubmed: 20921623
Arterioscler Thromb Vasc Biol. 2006 Jan;26(1):136-42
pubmed: 16254208
Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):708-15
pubmed: 20110570
Am J Transplant. 2007 Apr;7(4):779-88
pubmed: 17391123
Int J Mol Sci. 2020 Aug 06;21(16):
pubmed: 32781508
J Mol Cell Cardiol. 2015 May;82:218-27
pubmed: 25823396
Eur Heart J. 2009 May;30(10):1229-36
pubmed: 19329498
Circulation. 2009 Aug 18;120(7):577-84
pubmed: 19652094
Methods Mol Biol. 2012;757:261-78
pubmed: 21909918
Heart Fail Clin. 2006 Oct;2(4):379-93
pubmed: 17448426
Mol Metab. 2019 Dec;30:30-47
pubmed: 31767179
Hypertension. 2022 Aug;79(8):1724-1737
pubmed: 35549329
Endocrinology. 2012 Mar;153(3):1183-93
pubmed: 22234464
Blood. 2015 Aug 20;126(8):972-82
pubmed: 26022238
Exp Cell Res. 2015 Feb 1;331(1):152-163
pubmed: 25449697
PLoS One. 2012;7(7):e39980
pubmed: 22808080
Eur Heart J. 2003 Jul;24(13):1231-43
pubmed: 12831818
Circ Res. 2006 Nov 10;99(10):1044-59
pubmed: 17095733
J Bone Miner Res. 2015 Feb;30(2):357-68
pubmed: 25112732
Arterioscler Thromb Vasc Biol. 2018 Sep;38(9):2148-2159
pubmed: 30026273
Circ J. 2011;75(6):1305-13
pubmed: 21566338
J Am Heart Assoc. 2016 Nov 4;5(11):
pubmed: 27815266
Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):162-8
pubmed: 19023094
Eur J Vasc Endovasc Surg. 2016 May;51(5):623-31
pubmed: 26947538
Circulation. 2011 Mar 29;123(12):1316-25
pubmed: 21403093
J Cell Physiol. 2017 Aug;232(8):2125-2134
pubmed: 27800610
Hypertension. 2017 Dec;70(6):1148-1156
pubmed: 29061727
Hypertension. 2001 Oct;38(4):938-42
pubmed: 11641313
Sci Rep. 2021 Jan 28;11(1):2591
pubmed: 33510370
Arterioscler Thromb Vasc Biol. 2020 Apr;40(4):885-900
pubmed: 32160774
Eur J Clin Invest. 2013 May;43(5):439-48
pubmed: 23496280
Cancer Sci. 2017 Nov;108(11):2176-2186
pubmed: 28859238
Circulation. 2010 Jan 5;121(1):151-6
pubmed: 20026771
Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2168-2179
pubmed: 31034990
Eur J Radiol. 2008 Dec;68(3):471-5
pubmed: 17961946
Hypertension. 2015 Jul;66(1):158-66
pubmed: 25987661
Am Heart J. 2009 Oct;158(4):554-61
pubmed: 19781414
J Am Coll Cardiol. 2015 Oct 13;66(15):1643-53
pubmed: 26449133
Int J Cardiol. 2016 Aug 1;216:118-20
pubmed: 27153135
Biochem Biophys Res Commun. 2010 Jan 1;391(1):1087-92
pubmed: 20004646
BMC Nephrol. 2022 Apr 22;23(1):156
pubmed: 35459121
Biochem J. 2005 Oct 15;391(Pt 2):441-8
pubmed: 16060857
FASEB J. 2018 Aug;32(8):4459-4469
pubmed: 29547702
Circ Cardiovasc Qual Outcomes. 2017 Jun;10(6):
pubmed: 28600455
Can J Cardiol. 2014 Sep;30(9):962-70
pubmed: 24986049
Cardiovasc Res. 2016 Aug 1;111(3):262-73
pubmed: 27229458
Physiol Behav. 2016 Sep 1;163:7-16
pubmed: 27117816
J Biol Chem. 1993 May 15;268(14):10425-32
pubmed: 7683678
Cancers (Basel). 2018 Sep 18;10(9):
pubmed: 30231474
Circulation. 2003 May 6;107(17):2181-4
pubmed: 12719282
Clin Sci (Lond). 2018 May 8;132(9):909-923
pubmed: 29739822
J Cell Biochem. 2009 May 15;107(2):240-52
pubmed: 19288527
Atherosclerosis. 2012 Feb;220(2):552-6
pubmed: 22169111