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.
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.
|Hoganson, David M; Cooper, Dane A; Rich, Kimberly N et al. (2018) Flow Preservation of Umbilical Vein for Autologous Shunt and Cardiovascular Reconstruction. Ann Thorac Surg 105:1809-1818|
|Hagita, Sumihiko; Rogers, Maximillian A; Pham, Tan et al. (2018) Transcriptional control of intestinal cholesterol absorption, adipose energy expenditure and lipid handling by Sortilin. Sci Rep 8:9006|
|Schlotter, Florian; Halu, Arda; Goto, Shinji et al. (2018) Spatiotemporal Multi-Omics Mapping Generates a Molecular Atlas of the Aortic Valve and Reveals Networks Driving Disease. Circulation 138:377-393|
|Kim, Dae-Hee; Dal-Bianco, Jacob P; Aikawa, Elena et al. (2018) Mitral Valve Adaptation: Can We Win the Race? Circ Cardiovasc Imaging 11:e007642|
|Hutcheson, Joshua D; Aikawa, Elena (2018) Extracellular vesicles in cardiovascular homeostasis and disease. Curr Opin Cardiol 33:290-297|
|Goettsch, Claudia; Kjolby, Mads; Aikawa, Elena (2018) Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases. Arterioscler Thromb Vasc Biol 38:19-25|
|Itoh, Shinsuke; Mizuno, Ken; Aikawa, Masanori et al. (2018) Dimerization of sortilin regulates its trafficking to extracellular vesicles. J Biol Chem 293:4532-4544|
|Sena, Brena F; Figueiredo, Jose Luiz; Aikawa, Elena (2017) Cathepsin S As an Inhibitor of Cardiovascular Inflammation and Calcification in Chronic Kidney Disease. Front Cardiovasc Med 4:88|
|Bakhshian Nik, Amirala; Hutcheson, Joshua D; Aikawa, Elena (2017) Extracellular Vesicles As Mediators of Cardiovascular Calcification. Front Cardiovasc Med 4:78|
|Nagy, Edit; Lei, Yang; Martínez-Martínez, Eduardo et al. (2017) Interferon-? Released by Activated CD8+ T Lymphocytes Impairs the Calcium Resorption Potential of Osteoclasts in Calcified Human Aortic Valves. Am J Pathol 187:1413-1425|
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