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Osteopontin - CD44v6 Interaction Mediates Calcium Deposition via Phospho-Akt in Valve Interstitial Cells from patients with non-calcified Aortic Valve Sclerosis
Paolo Poggio1, Emanuela Branchetti1, Juan B. Grau1, Robert C. Gorman1, Joseph H. Gorman, III1, Micheal S. Sacks2, Joseph E. Bavaria1,
Giovanni Ferrari1.
1University of Pennsylvania, Philadelphia, PA, USA, 2University of Texas at Austin, Austin, TX, USA.

OBJECTIVE: Calcific Aortic Valve Disease (CAVD) is the most frequent valve disorder associated with surgical aortic valve replacement (AVR) in the US. With shifting demographics from an aging population, AVR is projected to reach more than 850,000 cases worldwide by 2050, from today's 300,000. While the final stages of the disease (Aortic Valve Stenosis) are well described, the cellular mechanisms responsible for the initial phases (Aortic Valve Sclerosis) remain largely unknown due to its subclinical presentation. In addition, sclerotic tissues are generally not available to investigators since these valves are not replaced until severe stenosis occurs. Osteopontin (OPN) is a phosphorylated-acidic-glycoprotein that accumulates within the aortic leaflets and labels valve interstitial cells (VICs) activation even in non-calcified asymptomatic patients. In recent works, we - and others - have demonstrated the capacity OPN to protect VICs against ectopic and dystrophic calcification. Here we unveil the specific interaction of OPN with CD44v6 and the related intracellular signaling pathway controlling calcium deposition in human VICs.
METHODS: Upon informed consent 23 patients and 4 controls were enrolled through the cardiac surgery and heart transplant programs. Human aortic valves and VICs were obtained and tested, for osteogenic transdifferentiation, ex vivo and in vitro, respectively. A uniaxial tensile bioreactor was used to test the effects of biomechanical stimulation of surgically resected tissues. OPN-CD44 functional interaction was analyzed using Proximity Ligation Assay and the intracellular signaling pathways were investigated.
RESULTS: First we demonstrated a specific OPN-CD44 functional interaction in early asymptomatic stage of CAVD. We then show that preventing OPN-CD44 interaction result in calcium accumulation of VIC obtained from non-calcified AVSc patients after treatments with BMP4. Finally, using neutralizing antibodies and general inhibitors of intracellular signaling pathways we unveil that Akt phosphorylation induced by OPN-CD44 is required to protect human sclerotic VICs from calcium deposition.
OBJECTIVE: Here we unveil a specific protein-protein association and intracellular signaling mechanisms of OPN, one of the early markers of CAVD. Understanding the molecular mechanisms of early VIC activation and calcium deposition in asymptomatic stage of CAVD could open new prospective for diagnosis and therapeutic intervention.

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