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Stenotic Aortic Valves Have Dysfunctional Mechanisms of Anti-inflammation: Implications for Aortic Stenosis
Joon H Lee, Xianzhong Meng, *Michael J Weyant, T. Brett Reece, *Joseph C Cleveland, Jr., *David A Fullerton
University of Colorado Health Science Center, Aurora, CO


OBJECTIVES:
The pathogenesis of aortic stenosis is incited by mechanisms of inflammation. Stimulation of pro-inflammatory mechanisms, Toll-like receptor 2 and 4 (TLR-2 and TLR-4) pathways, causes aortic valve interstitial cells (AVICs) to change to an osteogenic phenotype. A primary characteristic of this osteogenic phenotype is an increased production of the potent bone-forming protein, bone morphogenetic protein-2 (BMP-2). The net inflammatory state of any tissue is determined by the balance of pro- and anti-inflammatory mechanisms. To maintain inflammatory homeostasis, cells must produce anti-inflammatory cytokines when stimulated by pro-inflammatory cytokines. We examined this balance in AVICs. Interleukin-1 receptor antagonist (IL-1RA) is a potent anti-inflammatory cytokine. We hypothesized that the anti-inflammatory response to pro-inflammatory stimulation is impaired in aortic stenosis. In human aortic valve cells from normal and stenotic aortic valves, our purpose was to examine: (1) the production of IL-1RA and (2) the ability of IL-1RA to protect against the phenotypic change in AVIC when stimulated by pro-inflammatory mechanisms (TLR-2 and TLR-4).
METHODS:
AVICs were isolated from stenotic aortic valves resected at the time of aortic valve replacement for severe aortic stenosis (n=4). Control AVICs were isolated from normal aortic valves from explanted hearts during cardiac transplantation (n=4). IL-1RA production from AVIC cell lysates was determined (ELISA) after pro-inflammatory stimulation of TLR-2 (peptidoglycan, PGN, 10μg/mL) and TLR-4 (lipopolysaccharide, LPS, 200ng/mL) pathways. The ability of IL-1RA (100μg/mL) to protect against phenotype change (BMP-2 production) was determined by immunoblotting of cell lysates of normal AVICs stimulated by the pro-inflammatory pathways of TLR-2 (PGN, 10μg/mL) and TLR-4 (LPS 200ng/mL). Statistics were by ANOVA.
RESULTS:
The anti-inflammatory cytokine, IL-1RA, was significantly decreased in stenotic aortic valves. Untreated stenotic AVICs had undetectable levels of IL-1RA compared to 354.5 ± 12.9 pg/mL in controls (p≤0.05) (Figure 1). Further, production of IL-1RA in response to pro-inflammatory stimulation (TLR-2 and TLR-4 pathways) was impaired in stenotic valves compared to controls: TLR-2 stimulation and TLR-4 stimulation in controls yielded 3.2- and 1.96-fold greater increase in IL-1RA, respectively, over stenotic AVIC (p≤0.05). In normal AVICs, IL-1RA attenuated the TLR-2- and TLR-4-stimulated production of BMP-2 by 33% and 49%, respectively, (Figure 2).
CONCLUSIONS:
An imbalance of pro- and anti-inflammatory mechanisms produces an osteogenic phenotype in AVICs. Stenotic aortic valves have dysfunctional mechanisms of anti-inflammation. The potent anti-inflammatory cytokine, IL-1RA, was undetectable in stenotic aortic valves. Further, the production of IL-1RA in response to pro-inflammatory stimulation of TLR-2 and TLR-4 was significantly impaired in stenotic aortic valves. We conclude that impaired mechanisms of anti-inflammation contribute to the pathogenesis of aortic stenosis.

Figure 1. IL-1RA production by AVICs from stenotic and normal aortic valves.

Figure 2. Attenuation of BMP-2 production in normal AVIC by exogenous IL-1RA.
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