Sex-related Signalling Of Aldosterone/mineralocorticoid Receptor Pathway In Calcific Aortic Stenosis
Lara Matilla Cuenca1, Rafael Sadaba1, Eva Jover1, Mattie Garaikoetxea1, Vanessa Arrieta1, Amaia Garcia-Peña1, Adela Navarro1, Amaya Fernandez-Celis1, Alicia Gainza1, Virginia Álvarez1, Frederic Jaisser2, Natalia López-Andrés1.
1Navarrabiomed, Pamplona, Spain, 2Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Team Diabetes, metabolic diseases and comorbidities, F-75006, Paris, France.
OBJECTIVE: There are clear sex differences in the pathophysiology of aortic valve (AV) calcification in aortic stenosis (AS) patients. However, the molecular and cellular mechanisms underlying such sex differences have not been elucidated yet. Aldosterone (Aldo) promotes proteoglycan synthesis in valve interstitial cells (VICs) from mitral valves via its mineralocorticoid receptor (MR).We investigated the influence of sex in the role of Aldo/MR pathway in AV calcification in AS patients.
METHODS: 226 patients with severe AS undergoing surgical valve replacement were recruited. 200 AVs (121 men and 79 women) were used for ex vivo analyses and 26 AVs (14 men and 12 women) for in vitro experiments. AVs were evaluated by immunohistological and immunofluorescence techniques, western blot, PCR, ELISA and cytokine array.
RESULTS: MR was expressed by primary aortic VICs and in AVs from AS patients. MR expression was 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. MR antagonism (spironolactone) blocked all the above effects. Cytokine arrays showed intercellular adhesion molecule (ICAM)-1 and osteopontin to be specifically increased by Aldo in male VICs. In AVs from men, MR expression positively associated with both ICAM-1 and osteopontin.
CONCLUSIONS: These findings demonstrate that the Aldo/MR pathway could play a role in early stages of AS by promoting VICs activation and ulterior calcification. Importantly, Aldo/MR pathway is involved in early AV calcification only in men. Accordingly, MR antagonism emerges as a new sex-specific pharmacological treatment to prevent AV calcification in men.
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