Sex-Differences in Aortic Stenosis: Mechanistic Insights and Clinical Implications

Matilla, Lara; Garaikoetxea, Mattie; Arrieta, Vanessa; García-Peña, Amaia; Fernández‐Celis, Amaya; Navarro, Adela; Gainza, Alicia; Álvarez, Virginia; Sádaba, Rafael; Jover, Eva; López‐Andrés, Natalia

doi:10.3389/fcvm.2022.818371

Cited by 18 publications

(38 citation statements)

References 46 publications

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“…In our study, the FABP4 was evaluated in AVs, showing that it was overexpressed in leaflets from men compared to women. Interestingly, FABP4 was mainly expressed in the inflammatory foci (CD68+) and fibrocalcific regions, more predominant in AVs from men, as we have recently reported [ 9 ]. Interestingly, the FABP4 levels in the AVs were positively associated with inflammatory, apoptotic, and osteogenic markers in men, but not in women.…”

Section: Discussionsupporting

confidence: 58%

“…Human aortic VICs were isolated from 20 AVs (four women and 16 men) obtained during surgical AV replacement. VICs from each patient were isolated and individually assayed, as previously described [ 9 , 10 ]. In brief, AVs were minced and subjected to enzymatic digestion in buffered collagenase II solution (240 U/mg of tissue, Worthington Biochemical Corporation) for 1 h, and then pelleted by centrifugation.…”

Section: Methodsmentioning

confidence: 99%

“…Although clear sex-specific differences in the clinical presentation or patient management have been evidenced, the underlying sex-dependent mechanisms driving the pathogenesis of AS have not yet been explored in depth [ 7 , 8 ]. Recent histological characterization of AVs and in vitro studies in VICs have shown that men present increased inflammatory, apoptotic, and calcification processes than women as well as a decreased ECM remodeling [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

Garaikoetxea

Martín‐Núñez

Navarro

et al. 2022

IJMS

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Aortic stenosis (AS) is a fibrocalcific disease of the aortic valves (AVs). Sex-differences in AS pathophysiology have recently been described. High levels of fatty acid-binding protein 4 (FAPB4) in atherosclerotic plaques have been associated with increased local inflammation, endothelial dysfunction, and plaque vulnerability. FABP4 pharmacological blockade has been shown to be effective for the treatment of atherosclerosis by modulating metabolic and inflammatory pathways. We aimed to analyze the sex-specific expression of FABP4 in AS and its potential role as a therapeutic target. A total of 226 patients (61.5% men) with severe AS undergoing surgical AV replacement were recruited. The FABP4 levels were increased in the AVs of AS patients compared to the control subjects, showing greater expression in the fibrocalcific regions. Male AVs exhibited higher levels of FABP4 compared to females, correlating with markers of inflammation (IL-6, Rantes), apoptosis (Bax, caspase-3, Bcl-2), and calcification (IL-8, BMP-2 and BMP-4). VICs derived from AS patients showed the basal expression of FABP4 in vitro. Osteogenic media induced upregulation of intracellular and secreted FABP4 levels in male VICs after 7 days, along with increased levels of inflammatory, pro-apoptotic, and osteogenic markers. Treatment with BMS309403, a specific inhibitor of FABP4, prevented from all of these changes. Thus, we propose FABP4 as a new sex-specific pharmacological therapeutic target in AS.

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Section: Discussionsupporting

confidence: 58%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

Garaikoetxea

Martín‐Núñez

Navarro

et al. 2022

IJMS

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“…2 Accumulating evidence suggests that there are sex-related differences in the pathophysiology of AS. 3–6 Men exhibit higher degree of AV calcification than women for the same AS severity. 3,7 The understanding of the sex-specific cellular and molecular mechanisms in AS might help to identify specific therapeutic approaches to prevent or halt the progression of this pathophysiological condition.…”

mentioning

confidence: 99%

Sex-Related Signaling of Aldosterone/Mineralocorticoid Receptor Pathway in Calcific Aortic Stenosis

et al. 2022

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Background: There are sex differences in the pathophysiology of aortic valve (AV) calcification in patients with aortic stenosis, although the molecular and cellular mechanisms have not been elucidated. Aldosterone (Aldo) promotes proteoglycan synthesis in valve interstitial cells (VICs) from mitral valves via the mineralocorticoid receptor (MR). We investigated the influence of sex in the role of Aldo/MR pathway in AV alterations in patients with aortic stenosis. METHODS AND RESULTS: MR was expressed by primary aortic VICs and in AVs from patients with aortic stenosis. MR expression positively correlated with VIC activation markers in AVs from both sexes. However, MR expression was positively associated with molecules involved in AV calcification only in AV from men. Aldo enhanced VIC activation markers in cells from men and women. Interestingly, Aldo increased the expression of calcification markers only in VICs isolated from men. In female VICs, Aldo enhanced fibrotic molecules. MR antagonism (spironolactone) blocked all the above effects. Cytokine arrays showed ICAM (intercellular adhesion molecule)-1 and osteopontin to be specifically increased by Aldo in male VICs. In AVs from men, MR expression positively associated with both ICAM-1 (intercellular adhesion molecule-1) and osteopontin. Only in female VICs, estradiol treatment blocked Aldo-induced VICs activation, inflammation, and fibrosis. Conclusions: These findings demonstrate that the Aldo/MR pathway could play a role in early stages of aortic stenosis by promoting VICs activation, fibrosis, and ulterior calcification. Importantly, Aldo/MR pathway is involved in fibrosis in women and in early AV calcification only in men. Accordingly, MR antagonism emerges as a new sex-specific pharmacological treatment to prevent AV alterations.

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“…Although the mechanisms and effects differ between calcifying VSMCs and osteoblasts, an upregulated periostin expression was observed in both cell types during VSMC calcification and osteoblast differentiation [ 42 ]. Furthermore, an upregulated periostin expression was observed in calcifying dermal fibroblasts [ 43 ], calcified human aortic valves [ 44 ], atherosclerotic plaques [ 45 ] and left ventricular tissues of rats with chronic renal failure [ 46 ]. In rats, the left ventricular periostin expression was increased by angiotensin 2 or vasopressin, known stimulators of vascular calcification [ 3 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Periostin Augments Vascular Smooth Muscle Cell Calcification via β-Catenin Signaling

et al. 2022

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Medial vascular calcification is common in chronic kidney disease (CKD) and is closely linked to hyperphosphatemia. Vascular smooth muscle cells (VSMCs) can take up pro-calcific properties and actively augment vascular calcification. Various pro-inflammatory mediators are able to promote VSMC calcification. In this study, we investigated the effects and mechanisms of periostin, a matricellular signaling protein, in calcifying human VSMCs and human serum samples. As a result, periostin induced the mRNA expression of pro-calcific markers in VSMCs. Furthermore, periostin augmented the effects of β-glycerophosphate on the expression of pro-calcific markers and aggravated the calcification of VSMCs. A periostin treatment was associated with an increased β-catenin abundance as well as the expression of target genes. The pro-calcific effects of periostin were ameliorated by WNT/β-catenin pathway inhibitors. Moreover, a co-treatment with an integrin αvβ3-blocking antibody blunted the pro-calcific effects of periostin. The silencing of periostin reduced the effects of β-glycerophosphate on the expression of pro-calcific markers and the calcification of VSMCs. Elevated serum periostin levels were observed in hemodialysis patients compared with healthy controls. These observations identified periostin as an augmentative factor in VSMC calcification. The pro-calcific effects of periostin involve integrin αvβ3 and the activation of the WNT/β-catenin pathway. Thus, the inhibition of periostin may be beneficial to reduce the burden of vascular calcification in CKD patients.

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Sex-Differences in Aortic Stenosis: Mechanistic Insights and Clinical Implications

Cited by 18 publications

References 46 publications

Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

Sex-Related Signaling of Aldosterone/Mineralocorticoid Receptor Pathway in Calcific Aortic Stenosis

Periostin Augments Vascular Smooth Muscle Cell Calcification via β-Catenin Signaling

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