Calcific aortic valve disease (CAVD) is common in the elderly. CAVD progression to significant aortic stenosis occurs over years in most patients. This indolent course affords the opportunity for therapeutic intervention to halt the disease progression at an early stage. However, limited knowledge of mechanisms underlying CAVD progression impedes the development of effective pharmacological therapies. In the current funding period, our extensive studies have identified signaling mechanisms mediated by innate immune receptors, particularly TLR2 and TLR4, as regulators of the fibrogenic and osteogenic activities in human aortic valve interstitial cells (AVICs). We also discovered that oxidized low-density lipoprotein (oxLDL) and extracellular matrix (ECM) protein matrilin 2 function as damage-associated molecular patterns (DAMPs) in human AVICs, prompting differential cell activation with elevated fibrogenic and osteogenic activities. In addition we observed that human monocytes activated by TLR2 up-regulate AVIC expression of pro-fibrogenic and pro-osteogenic mediators via a paracrine mechanism. Planned studies in this renewal application will test the central hypothesis that distinct molecular mechanisms triggered by AVIC innate immune response elevate cellular and valvular fibrogenic and osteogenic activities through induction of cell activation and/or myofibroblastic transition. We further hypothesize that down- regulation of AVIC innate immune response has therapeutic potential to suppress valvular fibrosis and calcification. These hypotheses are based on our recent observation that oxLDL elevates AVIC fibrogenic and osteogenic activities through a myofibroblast transition-independent mechanism, whereas soluble matrilin 2 elevates these activities in human AVICs through inducing myofibroblastic transition. Moreover, we discovered that human AVICs express anti-aging protein Klotho. This anti-aging protein is capable of modulating AVIC innate immune response. Interestingly, Klotho levels are much lower in aortic valve tissues and AVICs from patients with CAVD, and Klotho insufficiency exacerbates valvular fibrogenic and osteogenic activities. This grant application will address: (1) the mechanisms underlying AVIC fibrogenic and osteogenic activities, (2) the mechanism by which Klotho insufficiency exacerbates AVIC fibrogenic and osteogenic activities, (3) anti- inflammatory approaches to up-regulate Klotho expression in aortic valve and (4) the therapeutic potential of Klotho to alleviate valvular fibrosis and calcification. This proposed work will provide mechanistic insights into the pathobiology of CAVD progression and identify therapeutic targets for pharmacological intervention to halt CAVD progression.

Public Health Relevance

Calcific aortic valve disease is the most common cardiovascular disease in the elderly. Progressive valvular thickening due to fibrosis and calcification eventually results in heart failure. Currently, aortic valve replacement or repair is the only available therapy. The major goals of this project are to elucidate the molecular mechanisms underlying valvular fibrosis and calcification and to identify targets for pharmacological intervention toward halting the progression of calcific aortic valve disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Evans, Frank
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University of Colorado Denver
Schools of Medicine
United States
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Cheng, Hui; Yao, Qingzhou; Song, Rui et al. (2017) Lysophosphatidylcholine activates the Akt pathway to upregulate extracellular matrix protein production in human aortic valve cells. J Surg Res 213:243-250
Zhan, Qiong; Song, Rui; Li, Fei et al. (2017) Double-stranded RNA upregulates the expression of inflammatory mediators in human aortic valve cells through the TLR3-TRIF-noncanonical NF-?B pathway. Am J Physiol Cell Physiol 312:C407-C417
Li, Fei; Yao, Qingzhou; Ao, Lihua et al. (2017) Klotho suppresses high phosphate-induced osteogenic responses in human aortic valve interstitial cells through inhibition of Sox9. J Mol Med (Berl) 95:739-751
Song, Rui; Fullerton, David A; Ao, Lihua et al. (2017) An epigenetic regulatory loop controls pro-osteogenic activation by TGF-?1 or bone morphogenetic protein 2 in human aortic valve interstitial cells. J Biol Chem 292:8657-8666
Li, Fei; Song, Rui; Ao, Lihua et al. (2017) ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells. Arterioscler Thromb Vasc Biol 37:1339-1351
Zeng, Qingchun; Song, Rui; Fullerton, David A et al. (2017) Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice. Proc Natl Acad Sci U S A 114:1631-1636
Zhan, Qiong; Zeng, Qingchun; Song, Rui et al. (2017) IL-37 suppresses MyD88-mediated inflammatory responses in human aortic valve interstitial cells. Mol Med 23:83-91