Abstract 14434: Oxidized Low Density Lipoprotein Elevates the Pro-osteogenic Activity in Human Aortic Valve Interstitial Cells via Innate Immune Receptors
Calcific aortic valve disease (CAVD) is a chronic pathological process involving inflammation, fibrosis and calcification. Pharmacological intervention for prevention of CAVD progression remains unavailable. Calcified aortic valves display higher levels of oxidized low-density lipoprotein (oxLDL), and oxLDL has the potential to interact with Toll-like receptors (TLRs). Interleukin (IL)-37 is an anti-inflammatory cytokine and has been shown to inhibit TLR4-mediated inflammatory responses. We tested the hypotheses that oxLDL induces the osteogenic responses in human aortic valve interstitial cells (AVICs) via TLRs and that IL-37 suppresses the responses and may have therapeutic potential for suppression of CAVD progression.
Methods and Results: Human AVICs from normal valves were treated with oxLDL (20-80 μg/ml) for 72 hours in vitro. OxLDL up-regulated the expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) in a dose-dependent fashion. Further, oxLDL induced NF-κB and ERK1/2 phosphorylation through a mechanism involving TLR 2 and TLR4, but not LOX-1. Inhibition of NF-κB or ERK1/2 reduced the effect of oxLDL on BMP-2 and ALP expression. Treatment with recombinant IL-37 suppressed oxLDL-induced NF-κB and ERK1/2 phosphorylation, resulting in marked reductions in BMP-2 and ALP levels, ALP activity and calcium deposit formation. To determine the effect of IL-37 on aortic valve lesions in vivo, we fed wild-type and IL-37 transgenic mice with a high fat diet for 8 weeks. Feeding wild-type mice with the high fat diet resulted in aortic valve thickening and expression of BMP-2 that are associated with accumulation of oxLDL in aortic valve leaflets. Transgenic expression of IL-37 prevented aortic valve thickening and BMP-2 expression caused by the high fat diet.
Conclusions: The results of this study show that oxLDL elevates the pro-osteogenic activity in human AVICs by activation of NF-κB and ERK1/2 through TLR2 and TLR4. IL-37 suppresses oxLDL-induced osteogenic responses in human AVICs and attenuate aortic valve thickening caused by a high fat diet in mice. These findings reveal a novel mechanism of CAVD pathogenesis and indicate that IL-37 has therapeutic potential for suppression of CAVD pathogenesis.
Author Disclosures: Q. Zeng: None. L. Ao: None. D. Fullerton: None. C. Dinarello: None. X. Meng: None.
- © 2016 by American Heart Association, Inc.