Sex-specific role of galectin-3 in aortic stenosis

被引:1
作者
Matilla, Lara [1 ]
Martin-Nunez, Ernesto [1 ]
Garaikoetxea, Mattie [1 ]
Navarro, Adela [1 ]
Tamayo, Ibai [2 ]
Fernandez-Celis, Amaya [1 ]
Gainza, Alicia [1 ]
Fernandez-Irigoyen, Joaquin [3 ]
Santamaria, Enrique [3 ]
Muntendam, Pieter [4 ]
Alvarez, Virginia [1 ]
Sadaba, Rafael [1 ]
Jover, Eva [1 ]
Lopez-Andres, Natalia [1 ]
机构
[1] Univ Publ Navarra UPNA, Hosp Univ Navarra HUN, Miguel Servet Fdn, Cardiovasc Translat Res,IdiSNA, C Irunlarrea 3, Pamplona 31008, Spain
[2] Univ Publ Navarra UPNA, Hosp Univ Navarra HUN, Res Methodol Unit, Navarrabiomed,IdiSNA, Pamplona, Spain
[3] Hosp Univ Navarra HUN, Univ Publ Navarra UPNA, Clin Neuroprote Unit, Navarrabiomed,IdiSNA, Pamplona, Spain
[4] G3 Pharmaceut, Burlington, MA USA
关键词
Galectin-3; Aortic stenosis; Sex differences; Valve interstitial cell; Inflammation; Calcification; Angiogenesis; HEART-FAILURE; CALCIFICATION; FIBROSIS; IMPACT;
D O I
10.1186/s13293-023-00556-1
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BackgroundAortic stenosis (AS) is characterized by inflammation, fibrosis, osteogenesis and angiogenesis. Men and women develop these mechanisms differently. Galectin-3 (Gal-3) is a pro-inflammatory and pro-osteogenic lectin in AS. In this work, we aim to analyse a potential sex-differential role of Gal-3 in AS.Methods226 patients (61.50% men) with severe AS undergoing surgical aortic valve (AV) replacement were recruited. In AVs, Gal-3 expression and its relationship with inflammatory, osteogenic and angiogenic markers was assessed. Valve interstitial cells (VICs) were primary cultured to perform in vitro experiments.ResultsProteomic analysis revealed that intracellular Gal-3 was over-expressed in VICs of male AS patients. Gal-3 secretion was also higher in men's VICs as compared to women's. In human AVs, Gal-3 protein levels were significantly higher in men, with stronger immunostaining in VICs with myofibroblastic phenotype and valve endothelial cells. Gal-3 levels in AVs were positively correlated with inflammatory markers in both sexes. Gal-3 expression was also positively correlated with osteogenic markers mainly in men AVs, and with angiogenic molecules only in this sex. In vitro, Gal-3 treatment induced expression of inflammatory, osteogenic and angiogenic markers in male's VICs, while it only upregulated inflammatory and osteogenic molecules in women-derived cells. Gal-3 blockade with pharmacological inhibitors (modified citrus pectin and G3P-01) prevented the upregulation of inflammatory, osteogenic and angiogenic molecules.ConclusionsGal-3 plays a sex-differential role in the setting of AS, and it could be a new sex-specific therapeutic target controlling pathological features of AS in VICs. Aortic stenosis (AS) is a condition that affects the aortic valves (AVs) of the heart and leads to death if untreated. Males and females show clear differences in the onset of AS, both clinically and in valve deterioration. In this study we identified galectin-3 (Gal-3) as a molecule involved in the development of AS alterations with different effects in men and women. We analyzed AVs of 226 patients (139 male and 87 female) with severe AS who underwent surgical AV replacement to study the association of Gal-3 with markers of mechanisms related to AS, such as inflammation, calcification and blood vessels formation. We performed experiments in valvular interstitial cells (VICs) to evaluate the impact of Gal-3 in these cells and its potential use as a therapeutic target. Our results showed that Gal-3 was more expressed in AVs and VICs of men over women. In AVs, Gal-3 levels were associated with inflammatory markers either in male and female, while they correlated with osteogenic markers mainly in men and with angiogenic only in male. The treatment of VICs with Gal-3 produced increased levels of inflammatory and osteogenic molecules by cells of both sexes, but of angiogenic markers only in male's. Pharmacological inhibition of Gal-3 prevented the increase of these pathological markers in VICs. Overall, our study indicates that Gal-3 is a molecule implicated in the setting of AS in a sex-differential way and its targeting may lead to a new sex-specific therapeutic option for AS treatment. The existence of a well-known sex dimorphism in the pathophysiological mechanisms of AS, leads to consider a possible differential role for Gal-3 in men and women AVs and VICs and in the pathological features of AS, such as inflammation, angiogenesis and calcification.Gal-3 expression in AVs and VICs is significantly higher in male AS patients than in female with the same AS severity.Gal-3 is predominantly expressed by activated VICs (vimentin+/alpha-SMA+) and endothelial cells (CD31+/VE-cadherin+) in men's AVs, while in women it is mainly expressed by quiescent VICs (vimentin+/alpha-SMA-) and endothelial cells.Gal-3 is directly associated with pathological features of AS in AVs and VICs but in a sex-differential way.Targeting Gal-3 inhibition may lead to a new sex-specific therapeutic for AS.
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