Calcific aortic valve disease (CAVD) affects a large number of people over age 65. Currently, aortic valve replacement surgery is the only available therapy for this disease. Pharmacological intervention of CAVD progression relies on better understanding of the underlying mechanism. Progressive valvular calcification is the main cause of CAVD progression. Elevated levels of bone morphogenetic protein-2 (BMP-2) and transforming growth factor-?1 (TGF-?1) in valvular tissue contribute to the mechanism of progressive aortic valve calcification, and the aortic valve interstitial cells (AVICs) play a critical role in valvular calcification via pro-osteogenic reprogramming. While BMP-2 and TGF-?1 induce AVIC pro- osteogenic reprogramming and myofibroblastic transition, the molecular mechanism underlying the actions of BMP-2 and TGF- ?1 on AVIC is not well understood, and the role of AVIC myofibroblastic transition in valvular calcification is unknown. We found that both BMP-2 and TGF-?1 up-regulate miR- 486 expression and down-regulate miR-204 expression in human AVICs. Further, co-expression of miR- 486 antagomir and 204 mimic suppresses the pro-osteogenic activity in AVICs of diseased human aortic valves, and miR-486 mimic and miR-204 antagomir elevate the levels of osteogenic transcription factors Runx2 and Osx. Further, miR-204 mimic and miR-486 antagomir synergizes in up-regulation of AVIC pro- osteogenic activity. Based on these novel findings, we hypothesize that miR-486 up-regulation and miR- 204 down-regulation promote aortic valve calcification. The major goals of this project are to elucidate the molecular mechanism of aortic valve calcification and to identify potential therapeutic targets for prevention of CAVD progression. To achieve these goals, we will address the following interrelated Specific Aims: 1) to determine the interaction of miR-486 and miR-204 in elevating the pro-osteogenic activity in human aortic valves and AVICs, 2) to test the hypothesis that miR-486 up-regulates human AVIC pro-osteogenic activity through promoting myofibroblastic transition, and 3) to elucidate the mechanism by which TGF-?1 and BMP-2 modulate miR-486 and miR-204 expression in human AVICs. The results of this project will help improve the understanding of the mechanism responsible for CAVD progression and may identify potential targets for pharmacological intervention.

Public Health Relevance

Calcific aortic valve disease is a leading cardiovascular disorder in the elderly. Progressive calcification of aortic valve leaflets causes the obstruction of blood flow and eventually results in heart failure. Currently, aortic valve replacement surgery is the only available therapy. Pharmacological intervention of this disease relies on better understanding of the mechanism underlying its progression. The major goals of this project are to elucidate the molecular mechanism that mediates aortic valve calcification and to identify potential therapeutic targets for prevention of the progression of aortic valve calcification. The findings of this project will help develop therapeutic strategies for pharmacologically slowing the progression of calcific aortic valve disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106582-07
Application #
9398146
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Evans, Frank
Project Start
2010-12-15
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Surgery
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
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:
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
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
Yao, Qingzhou; Song, Rui; Ao, Lihua et al. (2017) Neurotrophin 3 upregulates proliferation and collagen production in human aortic valve interstitial cells: a potential role in aortic valve sclerosis. Am J Physiol Cell Physiol 312:C697-C706
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
Song, Rui; Fullerton, David A; Ao, Lihua et al. (2017) Altered MicroRNA Expression Is Responsible for the Pro-Osteogenic Phenotype of Interstitial Cells in Calcified Human Aortic Valves. J Am Heart Assoc 6:
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; Zeng, Qingchun et al. (2015) Activation of TLR3 induces osteogenic responses in human aortic valve interstitial cells through the NF-?B and ERK1/2 pathways. Int J Biol Sci 11:482-93
Deng, Xin-Sheng; Meng, Xianzhong; Zeng, QingChun et al. (2015) Adult aortic valve interstitial cells have greater responses to toll-like receptor 4 stimulation. Ann Thorac Surg 99:62-71

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