This research project will test the hypothesis that, in the diabetic milieu, S100A9 induces the calcification potential of valvular interstitial cell (VIC)-derived matrix vesicles, precursors of microcalcification, offering the novel mechanism of calcific aortic valve disease (CAVD). Our pilot studies showed that S100A9 - a recently identified biomarker of acute cardiovascular events - is expressed by VIC and a component of matrix vesicles. The present study will examine in vivo and in vitro the role of interplay between S100A9 and matrix vesicles in aortic valve calcification in diabetes. A lack of high-resolution imaging techniques that can detect preclinical microcalcification is a critical barrier to the treatment of CAVD. Our published studie linked inflammation and calcification and showed that molecular imaging and micro-optical coherence tomography (?OCT) can identify microcalcification undetectable by other imaging modalities.
Specific Aim 1 will test the hypothesis in vivo that S100A9 promotes the formation of microcalcification in aortic valves of diabetic mice. We expect that genetic deletion of S100A9 will reduce diabetes-triggered matrix vesicle release, microcalcification, and CAVD.
Specific Aim 2 will develop novel imaging to evaluate quantitatively the impact of microcalcification on CAVD in diabetic mice and humans.
Specific Aim 3 will examine in vitro S100A9-mediated mechanisms for the formation of calcifying matrix vesicles. These complementary studies will advance the field by identifying the role of S100A9 in microcalcification. The findings from this project will bolster support for S100A9 as a therapeutic target for CAVD. In addition, this project will provide bases for the development of imaging for early diagnosis of CAVD in large animals and human patients.

Public Health Relevance

Calcific aortic valve disease (CAVD) is a global health burden in the United States and other aging societies. The incidence of CAVD is markedly higher in patients with diabetes, which affects 246 million people worldwide. However, CAVD has no effective therapeutic alternative to invasive and costly valve replacement. The primary goals of this project are to understand the mechanism of calcification in the diabetic milieu, and to discover new therapeutic targets. The lack of imaging technologies for the detection of subclinical calcification is a critical barrier to treatment of CAVD. Thus, we will also attempt to develop an imaging method for detection of early calcification, and will provide the basis for establishment of highly sensitive calcification imaging in the clinic.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114805-01
Application #
8352867
Study Section
Special Emphasis Panel (ZHL1-CSR-N (M1))
Program Officer
Evans, Frank
Project Start
2012-08-23
Project End
2017-06-30
Budget Start
2012-08-23
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$435,490
Indirect Cost
$148,365
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Rogers, Maximillian A; Maldonado, Natalia; Hutcheson, Joshua D et al. (2017) Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress. Circ Res 121:220-233
Hutcheson, Joshua D; Blaser, Mark C; Aikawa, Elena (2017) Giving Calcification Its Due: Recognition of a Diverse Disease: A First Attempt to Standardize the Field. Circ Res 120:270-273
Mosch, Josephin; Gleissner, Christian A; Body, Simon et al. (2017) Histopathological assessment of calcification and inflammation of calcific aortic valves from patients with and without diabetes mellitus. Histol Histopathol 32:293-306
Goettsch, Claudia; Iwata, Hiroshi; Hutcheson, Joshua D et al. (2017) Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men. Arterioscler Thromb Vasc Biol 37:1005-1011
Bakhshian Nik, Amirala; Hutcheson, Joshua D; Aikawa, Elena (2017) Extracellular Vesicles As Mediators of Cardiovascular Calcification. Front Cardiovasc Med 4:78
Aikawa, Elena; Libby, Peter (2017) A Rock and a Hard Place: Chiseling Away at the Multiple Mechanisms of Aortic Stenosis. Circulation 135:1951-1955
Iwata, Hiroshi; Goettsch, Claudia; Sharma, Amitabh et al. (2016) PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation. Nat Commun 7:12849

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