Activation profiles of monocyte-macrophages and HDL function in healthy women in relation to menstrual cycle and in polycystic ovary syndrome patients
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Hormonal status and menopause affect human macrophage function and cardiometabolic risk. In polycystic ovary syndrome (PCOS) patients the cardiometabolic risk increases through mechanisms that are largely unknown. We tested the hypotheses that macrophage activation is influenced by menstrual cycle and that ovarian dysfunction in PCOS patients is associated with altered macrophage inflammatory responses and cholesterol efflux capacity of serum HDL.
Blood samples were obtained in the follicular and luteal phases from cycling women (n = 10) and on a single visit from PCOS patients with ovarian dysfunction (n = 11). Monocyte-derived macrophage activation and monocyte subsets were characterized ex vivo using flow cytometry. The capacity of HDL to promote cell cholesterol efflux through the main efflux pathways, namely aqueous diffusion, ATP-binding cassette A1 and G1, was also evaluated.
Hormone and metabolic profiles differed as expected in relation to menstrual cycle and ovulatory dysfunction. Overall, macrophage responses to activating stimuli in PCOS patients were blunted compared with cycling women. Macrophages in the follicular phase were endowed with enhanced responsiveness to LPS/interferon-γ compared with the luteal phase and PCOS. These changes were not related to baseline differences in monocytes. HDL cholesterol efflux capacity through multiple pathways was significantly impaired in PCOS patients compared to healthy women, at least in part independent from lower HDL-cholesterol levels.
Regular menstrual cycles entailed fluctuations in macrophage activation. Such dynamic pattern was attenuated in PCOS. Along with impaired HDL function, this may contribute to the increased cardiometabolic risk associated with PCOS.
KeywordsMacrophages Macrophage activation Cholesterol efflux Polycystic ovary syndrome Menstrual cycle Monocytes
We wish to thank Dr. Fabrizio Veglia for his valuable help in statistical analyses of HDL CEC data.
G.P.F., C.B., and A.C. conceived the idea and planned the experiments. R.M., M.B., S.P., C.S., and G.P.F. conducted the clinical part of the study, S.T. and R.C performed cell culture and flow cytometry analyses, S.T. and G.P.F. carried out statistical analysis, M.P.A., N.R., and F.B performed CEC and intracellular cholesterol assays and refined statistical analyses, M.P. was responsible for laboratory medicine data. A.C. wrote the draft and all authors made substantial contributions to the final manuscript.
This study was funded by institutional funding to M.P., C.B., C.S., F.B., G.P.F., and A.C.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of Padova University Hospital Ethics Committee and with the 1964 Helsinki declaration and its later amendments.
Informed consent was obtained from all individual participants included in the study.
- 1.E.J. Benjamin, S.S. Virani, C.W. Callaway, et al. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 137, e67–e492 (2018)CrossRefGoogle Scholar
- 4.R.A. Wild, E. Carmina, E. Diamanti-Kandarakis, A. Dokras, H.F. Escobar-Morreale, W. Futterweit, R. Lobo, R.J. Norman, E. Talbott, D.A. Dumesic Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J. Clin. Endocrinol. Metab. 95(5), 2038–2049 (2010)CrossRefGoogle Scholar
- 9.A. Toniolo, G.P. Fadini, S. Tedesco, R. Cappellari, E. Vegeto, A. Maggi, A. Avogaro, C. Bolego, A. Cignarella Alternative activation of human macrophages is rescued by estrogen treatment in vitro and impaired by menopausal status. J. Clin. Endocrinol. Metab. 100(1), E50–58 (2015)CrossRefGoogle Scholar
- 17.A.V. Khera, M. Cuchel, M. de la Llera-Moya, A. Rodrigues, M.F. Burke, K. Jafri, B.C. French, J.A. Phillips, M.L. Mucksavage, R.L. Wilensky, E.R. Mohler, G.H. Rothblat, D.J. Rader Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364(2), 127–135 (2011)CrossRefGoogle Scholar
- 18.A.V. Khera, O.V. Demler, S.J. Adelman, H.L. Collins, R.J. Glynn, P.M. Ridker, D.J. Rader, S. Mora Cholesterol efflux capacity, high-density lipoprotein particle number, and incident cardiovascular events: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). Circulation 135(25), 2494–2504 (2017)CrossRefGoogle Scholar
- 23.A. Dokras, M. Playford, P.M. Kris-Etherton, A.R. Kunselman, C.M. Stetter, N.I. Williams, C.L. Gnatuk, S.J. Estes, D.B. Sarwer, K.C. Allison, C. Coutifaris, N. Mehta, R.S. Legro Impact of hormonal contraception and weight loss on high-density lipoprotein cholesterol efflux and lipoprotein particles in women with polycystic ovary syndrome. Clin Endocrinol. 86, 739–746 (2017)CrossRefGoogle Scholar
- 25.S. Tedesco, M. Zusso, L. Facci, A. Trenti, C. Boscaro, F. Belluti, G.P. Fadini, S.D. Skaper, P. Giusti, C. Bolego, A. Cignarella Bisdemethoxycurcumin and its cyclized pyrazole analogue differentially disrupt lipopolysaccharide signalling in human monocyte-derived macrophages. Mediators. Inflamm. 2018, 2868702 (2018)CrossRefGoogle Scholar
- 26.S. Tedesco, F. De Majo, J. Kim, A. Trenti, L. Trevisi, G.P. Fadini, C. Bolego, P.W. Zandstra, A. Cignarella, L. Vitiello Convenience versus biological significance: are PMA-differentiated THP-1 cells a reliable substitute for blood-derived macrophages when studying in vitro polarization? Front. Pharmacol. 9, 71 (2018)CrossRefGoogle Scholar
- 27.G.P. Fadini, S.V. de Kreutzenberg, E. Boscaro, M. Albiero, R. Cappellari, N. Kränkel, U. Landmesser, A. Toniolo, C. Bolego, A. Cignarella, F. Seeger, S. Dimmeler, A. Zeiher, C. Agostini, A. Avogaro An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy. Diabetologia 56(8), 1856–1866 (2013)CrossRefGoogle Scholar
- 30.N. Ronda, D. Greco, M.P. Adorni, F. Zimetti, E. Favari, G. Hjeltnes, K. Mikkelsen, M.O. Borghi, E.G. Favalli, R. Gatti, I. Hollan, P.L. Meroni, F. Bernini Newly identified antiatherosclerotic activity of methotrexate and adalimumab: complementary effects on lipoprotein function and macrophage cholesterol metabolism. Arthritis Rheumatol. 67(5), 1155–1164 (2015)CrossRefGoogle Scholar
- 31.L. Pisciotta, E. Favari, L. Magnolo, S. Simonelli, M.P. Adorni, R. Sallo, T. Fancello, I. Zavaroni, D. Ardigò, F. Bernini, L. Calabresi, G. Franceschini, P. Tarugi, S. Calandra, S. Bertolini Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. Circ Cardiovasc Genet. 5(1), 42–50 (2012)CrossRefGoogle Scholar
- 37.L. Ibáñez, S.E. Oberfield, S. Witchel, R.J. Auchus, R.J. Chang, E. Codner, P. Dabadghao, F. Darendeliler, N.S. Elbarbary, A. Gambineri, C. Garcia Rudaz, K.M. Hoeger, A. López-Bermejo, K. Ong, A.S. Peña, T. Reinehr, N. Santoro, M. Tena-Sempere, R. Tao, B.O. Yildiz, H. Alkhayyat, A. Deeb, D. Joel, R. Horikawa, F. de Zegher, P.A. Lee An International Consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm. Res. Paediatr. 88(6), 371–395 (2017)CrossRefGoogle Scholar
- 39.M. Karadeniz, M. Erdoğan, Z. Ayhan, M. Yalcin, M. Olukman, S. Cetinkalp, G.E. Alper, Z. Eroglu, A. Tetik, V. Cetintas, A.G. Ozgen, F. Saygili, C. Yilmaz Effect of G2706A and G1051A polymorphisms of the ABCA1 gene on the lipid, oxidative stress and homocystein levels in Turkish patients with polycystic ovary syndrome. Lipids. Health Dis. 10, 193 (2011)CrossRefGoogle Scholar