(655b) Toward the Incorporation of Female Sex and Estradiol in Computational Drug Target Identification Platforms for Calcific Aortic Valve Disease

Calcific aortic valve disease (CAVD) progresses from mild valve thickening to impaired leaflet motion. The current consensus on the disease mechanism involves dyslipidemia and endothelial dysfunction followed by inflammatory signaling, ultimately resulting in fibrosis and calcification. Ideally, this disease process could be halted or reversed through pharmaceutical intervention; however, clinical trials of lipid-lowering therapy, osteoporosis drugs, and other drug classes have either failed to show efficacy for slowing the progression of CAVD or are still under evaluation [1]. Despite ongoing efforts, there are no FDA-approved therapeutics to date that delay, halt, or reverse the progression of CAVD.

Female sex and estrogen have been reported to protect against CAVD development [2]; however, the precise cellular mechanisms for this protection are only now beginning to be unraveled. Recently, cellular sex was reported to influence interferon signaling pathways in the valve interstitial cells [3], [4] - the cells largely responsible for the fibro-calcification seen in CAVD. In addition to inflammatory inputs, female sex also tempers transforming growth factor pathways that lead to fibrosis [5]. We have developed first generation computational platforms for drug target identification in CAVD based on dynamic computational models of cell signaling processes that incorporate such observations of cellular sex differences along with our own observations of estrogen-mediated crosstalk. Our early computational and experimental results indicate that estrogen dampens the interferon response and estrogen and cellular sex synergize to reduce fibrotic responses. By learning from natural protection mechanisms offered by female sex and estrogens and further quantifying these effects with computational modeling, this approach sheds light on particular protection mechanisms that may serve as future drug targets.

References

[1] X. Qian, L. Xu, B. Geng, F. Li, and N. Dong, “Navigating the Landscape of Translational Medicine of Calcific Aortic Valve Disease,” JACC: Asia, vol. 5, no. 4, pp. 503–515, Apr. 2025, doi: 10.1016/j.jacasi.2025.01.014.

[2] V. I. Summerhill, D. Moschetta, A. N. Orekhov, P. Poggio, and V. A. Myasoedova, “Sex-Specific Features of Calcific Aortic Valve Disease,” IJMS, vol. 21, no. 16, p. 5620, Aug. 2020, doi: 10.3390/ijms21165620.

[3] I. Parra-Izquierdo et al., “Calcification Induced by Type I Interferon in Human Aortic Valve Interstitial Cells Is Larger in Males and Blunted by a Janus Kinase Inhibitor,” ATVB, vol. 38, no. 9, pp. 2148–2159, Sep. 2018, doi: 10.1161/ATVBAHA.118.311504.

[4] I. Parra-Izquierdo et al., “Lipopolysaccharide and interferon-γ team up to activate HIF-1α via STAT1 in normoxia and exhibit sex differences in human aortic valve interstitial cells,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1865, no. 9, pp. 2168–2179, Sep. 2019, doi: 10.1016/j.bbadis.2019.04.014.

[5] E. Le Nezet, C. Marqueze-Pouey, I. Guisle, and M.-A. Clavel, “Molecular Features of Calcific Aortic Stenosis in Female and Male Patients,” CJC Open, vol. 6, no. 9, pp. 1125–1137, Sep. 2024, doi: 10.1016/j.cjco.2024.06.002.