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1 Surgery, University of Colorado, Denver, Colorado, United States; Department of Surgery, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, United States
2 Surgery, UCHSC, Denver, Colorado, United States
3 Surgery, University of Colorado Health Sciences Center, 4200 East 9th Avenue #C320, Denver, Colorado, 80262, United States
4 Department of Surgery, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, United States
5 University of Colorado HSC, United States; University of Colorado HSC
* To whom correspondence should be addressed. E-mail: xianzhong.meng{at}uchsc.edu.
Calcific aortic valve stenosis is the most common indication for surgical valve replacement. Inflammation appears to be one of the mechanisms involved in aortic valve calcification, and valve interstitial cells seem to contribute to that process. Although Toll-like receptors (TLRs) play an important role in the cellular inflammatory response, it is unknown whether human aortic valve interstitial cells (HAVICs) express functional TLRs. We examined the expression of TLR2 and TLR4 in human aortic valve leaflets and in isolated HAVICs, and analyzed the response of cultured HAVICs to the TLR2 and TLR4 agonists peptidoglycan (PGN) and lipopolysaccharide (LPS). Abundant TLR2 and TLR4 proteins were found in human aortic valve leaflets and in isolated HAVICs, and both receptors were detected in the membrane and cytoplasm of cultured HAVICs. Stimulation by either PGN or LPS resulted in the activation of the NF-
B signaling pathway and the production of multiple pro-inflammatory mediators, including IL-6, IL-8 and ICAM-1. In addition, stimulation by either PGN or LPS up-regulated the expression of BMP-2 and Runx2, factors associated with osteogenesis. This study demonstrates for the first time that HAVICs express TLR2 and TLR4, and that stimulation of HAVICs by PGN or LPS induces the expression of pro-inflammatory mediators and the up-regulation of osteogenesis-associated factors. These results suggest that TLR2 and TLR4 may play a role in aortic valve inflammation and stenosis.
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