Preferential Activation of SMAD1/5/8 on the Fibrosa Endothelium in Calcified Human Aortic Valves - Association with Low BMP Antagonists and SMAD6

• Type of Material: Article
• Authors: Randall F. Ankeny, Georgia Institute of Technology; Vinod Thourani, Emory University; Daiana Weiss, Emory University; J David Vega, Emory University; W Taylor, Emory University; Hanjoong Jo, Emory University
• Language: English
• Date: 2011-06-15
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2011 Ankeny et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0020969
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 6
• Issue: 6
• Start Page: e20969
• End Page: e20969
• Grant/Funding Information: Imaging studies were performed in part through the use of the Emory Internal Medicine Imaging Core, (supported by NIH grants PO1 HL05800 and PO1 HL075209).; This work was supported by funding from National Institutes of Health grants HL75209, HL87012, and HL80711, and WCU Program (R31-2008-000-10010-0) (HJ), as well as an American Heart Association pre-doctoral fellowship 0715417B (RFA).
• Keywords: SPEMANN ORGANIZER; Cardiology; ATHEROSCLEROSIS; Calcification; CAROTID BIFURCATION; FLOW; SHEAR-STRESS; STENOSIS; BONE MORPHOGENIC PROTEIN-4; Immunohistochemistry techniques; EARLY LESION; Cardiac transplantation; CELLS; Multidisciplinary Sciences; Alizarin staining; Phosphorylation; Science & Technology; Surgical and invasive medical procedures; BMP signaling; Endothelium
• Research Categories: Engineering, Biomedical; Health Sciences, Medicine and Surgery

Abstract

Background: Aortic valve (AV) calcification preferentially occurs on the fibrosa side while the ventricularis side remains relatively unaffected. Here, we tested the hypothesis that side-dependent activation of bone morphogenic protein (BMP) pathway in the endothelium of the ventricularis and fibrosa is associated with human AV calcification. Methods and Results: Human calcified AVs obtained from AV replacement surgeries and non-calcified AVs from heart transplantations were used for immunohistochemical studies. We found SMAD-1/5/8 phosphorylation (a canonical BMP pathway) was higher in the calcified fibrosa than the non-calcified fibrosa while SMAD-2/3 phosphorylation (a canonical TGFβ pathway) did not show any difference. Interestingly, we found that BMP-2/4/6 expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both calcified and non-calcified AV cusps; however, BMP antagonists (crossvienless-2/BMPER and noggin) expression was significantly higher on the ventricularis endothelium compared to the fibrosa in both disease states. Moreover, significant expression of inhibitory SMAD-6 expression was found only in the non-calcified ventricularis endothelium. Conclusions: SMAD-1/5/8 is preferentially activated in the calcified fibrosa endothelium of human AVs and it correlates with low expression of BMP antagonists and inhibitory SMAD6. These results suggest a dominant role of BMP antagonists in the side-dependent calcification of human AVs.