Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis

• Published in: Cardiovascular research Vol. 98; no. 3; pp. 402 - 410
• Main Authors: Poggio, Paolo, Sainger, Rachana, Branchetti, Emanuela, Grau, Juan B, Lai, Eric K, Gorman, Robert C, Sacks, Michael S, Parolari, Alessandro, Bavaria, Joseph E, Ferrari, Giovanni
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-06-2013
• Subjects: Adult; Aged; Aged, 80 and over; Aortic Valve - metabolism; Aortic Valve - pathology; Aortic Valve Stenosis - genetics; Aortic Valve Stenosis - metabolism; Aortic Valve Stenosis - pathology; Aortic Valve Stenosis - prevention & control; Bioreactors; Bone Morphogenetic Protein 4 - metabolism; Calcinosis - genetics; Calcinosis - metabolism; Calcinosis - pathology; Calcinosis - prevention & control; Carrier Proteins - metabolism; Case-Control Studies; Cell Transdifferentiation; Cells, Cultured; Disease Progression; Female; Gene Expression Regulation; Humans; Male; Mechanotransduction, Cellular; Middle Aged; Original; Osteogenesis - genetics; Phenotype; Pressure; Recombinant Proteins - metabolism; Sclerosis; Tissue Culture Techniques; Tissue Engineering - methods; Tissue Scaffolds; Young Adult; Valve interstitial cells; Bone morphogenetic protein 4; Calcific aortic stenosis; Aortic valve sclerosis
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvt055

Aortic valve sclerosis (AVSc) is a hallmark of several cardiovascular conditions ranging from chronic heart failure and myocardial infarction to calcific aortic valve stenosis (AVS). AVSc, present in 25-30% of patients over 65 years of age, is characterized by thickening of the leaflets with marginal effects on the mechanical proprieties of the valve making its presentation asymptomatic. Despite its clinical prevalence, few studies have investigated the pathogenesis of this disease using human AVSc specimens. Here, we investigate in vitro and ex vivo BMP4-mediated transdifferentiation of human valve interstitial cells (VICs) towards an osteogenic-like phenotype in AVSc.
Human specimens from 60 patients were collected at the time of aortic valve replacement (AVS) or through the heart transplant programme (Controls and AVSc). We show that non-calcified leaflets from AVSc patients can be induced to express markers of osteogenic transdifferentiation and biomineralization through the combinatory effect of BMP4 and mechanical stimulation. We show that BMP4 antagonist Noggin attenuates VIC activation and biomineralization. Additionally, patient-derived VICs were induced to transdifferentiate using either cell culture or a Tissue Engineering (TE) Aortic Valve model. We determine that while BMP4 alone is not sufficient to induce osteogenic transdifferentiation of AVSc-derived cells, the combinatory effect of BMP4 and mechanical stretch induces VIC activation towards a phenotype typical of late calcified stage of the disease.
This work demonstrates, for the first time using AVSc specimens, that human sclerotic aortic valves can be induced to express marker of osteogenic-like phenotype typical of advanced severe aortic stenosis.