Discipline: Biological Sciences
Subcategory: Biomedical Engineering
Session: 1
Room: Virginia A
LaTonya Simon - University of Wisconsin-Madison
Co-Author(s): Kristyn Masters, University of Wisonsin-Madison, WI
Calcific aortic valve disease (CAVD) presents twice as often in males as females. Furthermore, recent evidence suggests sex-related differences in CAVD pathogenesis. For the same degree of stenosis, males exhibit greater amounts of calcium deposition while females typically exhibit greater levels of fibrosis [1]. Fibrosis and calcification in the valve are influenced by local inflammation and the production of inflammatory factors, which also serve as hallmarks of CAVD pathogenesis [2]. Sex bias in inflammation progression has been observed in other diseases, and understanding the inflammatory potential of male and female valvular interstitial cells (VICs) may help to elucidate sex-specific CAVD progression [3]. We hypothesize that male and female VICs differentially regulate inflammatory cytokine production by macrophages. VICs from the aortic heart valves of male and female pigs were grown in DMEM supplemented with 2% fetal bovine serum (control VICs) or DMEM supplemented with 2% fetal bovine serum and tumor necrosis factor-alpha (TNFα; primed VICs). Culture media was then collected to assess for inflammatory cytokine production or to treat adherent macrophage-like THP-1 cells. Prior to treatment with VIC conditioned media, monocytic THP-1 cells were treated with phorbol 12-myristate 13-acetate (PMA) to induce differentiation and adherence. M0 macrophages were treated with VIC-conditioned media and then evaluated for pro-inflammatory and anti-inflammatory phenotype markers. No sex bias was observed in the ability of media conditioned by control VICs to stimulate inflammatory cytokine expression by THP-1 cells. However, priming of VICs with TNFα not only increased cytokine expression by THP-1 cells, but did so in a sex-dependent manner. When macrophages were treated with conditioned media from TNFα-treated male VICs, expression of the pro-inflammatory cytokine IL-6 was upregulated to a greater extent than observed for the female VIC condition. Media from primed male VICs also elicited increased THP-1 expression of the anti-inflammatory cytokine IL-10, although to a lesser extent than observed for the pro-inflammatory factors. Media from primed female VICs did not affect IL-10 expression by THP-1 cells. These results suggest that, while males yield more robust pro-inflammatory factor expression than females, it may be offset by increases in anti-inflammatory cytokines, whereas females show solely increases in the expression of pro-inflammatory factors. The differential ability of male and female VICs to alter the inflammatory cytokine profile of macrophages supports the hypothesis that males and females may differentially regulate inflammation in the context of CAVD. Future work will look to investigate the inflammatory progression within the extracellular matrix of native valves. References: [1] Louis S et al., CircResAHA (2017) 120: 681-691 [2] Coté N et al., Inflammation (2013) 36: 573-581 [3] DeLisa F., Clin Med Insights Cardiol (2014) 8: 49-59
Funder Acknowledgement(s): This research was supported by R21EB019508, the National Institute of General Medical Sciences of the National Institutes of Health under award number R25GM083252, and the National Science Foundation under Grant No. 1400815. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health nor the National Science Foundation.
Faculty Advisor: Kristyn Masters, kmasters@wisc.edu
Role: I conducted all parts of the research presented here.