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PRE-CLINICAL RESEARCH

Pro-Osteogenic Phenotype of Human Aortic Valve Interstitial Cells Is Associated With Higher Levels of Toll-Like Receptors 2 and 4 and Enhanced Expression of Bone Morphogenetic Protein 2

Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado Denver, Denver, Colorado

Manuscript received July 22, 2008; revised manuscript received September 22, 2008, accepted September 29, 2008.

^_* Reprint requests and correspondence: Dr. Xianzhong Meng, Department of Surgery, Box C-320, 12700 East 19th Avenue, Aurora, Colorado 80045 (Email: Xianzhong.meng{at}uchsc.edu).

Objectives: Our aim was to determine whether aortic valve interstitial cells (AVICs) and pulmonary valve interstitial cells (PVICs) differ in expression of toll-like receptor (TLR)2 and TLR4, response to TLR agonists, and osteogenic phenotypic changes.

Background: Calcific stenosis occurs frequently in aortic valves but rarely in pulmonary valves. Studies have implicated AVICs in the inflammation associated with calcification and progression to stenosis. We previously reported that human AVICs express functional TLR2 and TLR4 and that stimulation of these receptors induces pro-osteogenic factor expression.

Methods: Human aortic and pulmonary valve leaflets from the same heart were collected and interstitial cells isolated.

Results: Aortic valves express more TLR2 and TLR4, in both tissue and isolated interstitial cells, than pulmonary valves. After stimulation with TLR2 and TLR4 agonists, AVICs express higher levels of pro-inflammatory and pro-osteogenic mediators (bone morphogenetic protein [BMP]-2, runt-related transcription factor 2) and greater osteogenic phenotypic changes (alkaline phosphatase [ALP] activity, calcified nodule formation) than PVICs. Silencing TLR2 and TLR4 in AVICs reduced BMP-2 expression and ALP activity to PVIC levels. ALP activity in AVICs induced by TLR2 and TLR4 agonists was abolished by BMP antagonism with Noggin and mimicked by stimulation with recombinant BMP-2. AVICs isolated from stenotic valves had greater expression of TLR2 and TLR4 and a greater BMP-2 response than AVICs from normal valves.

Conclusions: Greater expression of TLR2 and TLR4 and greater pro-inflammatory and pro-osteogenic responses to TLR2 and TLR4 agonists in AVICs than PVICs are associated with osteogenic phenotypic changes. These innate immune receptors may play a critical role in aortic valve calcification and stenosis.

Key Words: valves • stenosis • receptors • inflammation

Abbreviations and Acronyms   ALP = alkaline phosphatase   AVIC = aortic valve interstitial cell   BMP = bone morphogenetic protein   PVIC = pulmonary valve interstitial cell   Runx2 = runt-related transcription factor 2   TLR = toll-like receptor   VIC = valve interstitial cell

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