Osteopontin-CD44v6 interaction mediates calcium deposition via phospho-akt in valve interstitial cells from patients with noncalcified aortic valve sclerosis

Paolo Poggio, Emanuela Branchetti, Juan B. Grau, Eric K. Lai, Robert C. Gorman, Joseph H. Gorman, Michael S. Sacks, Joseph E. Bavaria, Giovanni Ferrari

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

OBJECTIVE - The activation of valve interstitial cells (VICs) toward an osteogenic phenotype characterizes aortic valve sclerosis, the early asymptomatic phase of calcific aortic valve disease. Osteopontin is a phosphorylated acidic glycoprotein that accumulates within the aortic leaflets and labels VIC activation even in noncalcified asymptomatic patients. Despite this, osteopontin protects VICs against in vitro calcification. Here, we hypothesize that the specific interaction of osteopontin with CD44v6, and the related intracellular pathway, prevents calcium deposition in human-derived VICs from patients with aortic valve sclerosis. APPROACH AND RESULTS - On informed consent, 23 patients and 4 controls were enrolled through the cardiac surgery and heart transplant programs. Human aortic valves and VICs were tested for osteogenic transdifferentiation, ex vivo and in vitro. Osteopontin-CD44 interaction was analyzed using proximity ligation assay and the signaling pathways investigated. A murine model based on angiotensin II infusion was used to mimic early pathological remodeling of the aortic valves. We report osteopontin-CD44 functional interaction as a hallmark of early stages of calcific aortic valve disease. We demonstrated that osteopontin-CD44 interaction mediates calcium deposition via phospho-Akt in VICs from patients with noncalcified aortic valve sclerosis. Finally, microdissection analysis of murine valves shows increased cusp thickness in angiotensin II-treated mice versus saline infused along with colocalization of osteopontin and CD44 as seen in human lesions. CONCLUSIONS - Here, we unveil a specific protein-protein association and intracellular signaling mechanisms of osteopontin. Understanding the molecular mechanisms of early VIC activation and calcium deposition in asymptomatic stage of calcific aortic valve disease could open new prospective for diagnosis and therapeutic intervention.

Original languageEnglish
Pages (from-to)2086-2094
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume34
Issue number9
DOIs
Publication statusPublished - 2014

Fingerprint

Osteopontin
Sclerosis
Aortic Valve
Calcium
Aortic Diseases
Angiotensin II
Intracellular Signaling Peptides and Proteins
Microdissection
Informed Consent
Thoracic Surgery
Ligation
Glycoproteins
Transplants
Phenotype

Keywords

  • aortic valve
  • osteopontin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Osteopontin-CD44v6 interaction mediates calcium deposition via phospho-akt in valve interstitial cells from patients with noncalcified aortic valve sclerosis. / Poggio, Paolo; Branchetti, Emanuela; Grau, Juan B.; Lai, Eric K.; Gorman, Robert C.; Gorman, Joseph H.; Sacks, Michael S.; Bavaria, Joseph E.; Ferrari, Giovanni.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 34, No. 9, 2014, p. 2086-2094.

Research output: Contribution to journalArticle

Poggio, Paolo ; Branchetti, Emanuela ; Grau, Juan B. ; Lai, Eric K. ; Gorman, Robert C. ; Gorman, Joseph H. ; Sacks, Michael S. ; Bavaria, Joseph E. ; Ferrari, Giovanni. / Osteopontin-CD44v6 interaction mediates calcium deposition via phospho-akt in valve interstitial cells from patients with noncalcified aortic valve sclerosis. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2014 ; Vol. 34, No. 9. pp. 2086-2094.
@article{9d8f405182d242cf9de04ef0c7e285d1,
title = "Osteopontin-CD44v6 interaction mediates calcium deposition via phospho-akt in valve interstitial cells from patients with noncalcified aortic valve sclerosis",
abstract = "OBJECTIVE - The activation of valve interstitial cells (VICs) toward an osteogenic phenotype characterizes aortic valve sclerosis, the early asymptomatic phase of calcific aortic valve disease. Osteopontin is a phosphorylated acidic glycoprotein that accumulates within the aortic leaflets and labels VIC activation even in noncalcified asymptomatic patients. Despite this, osteopontin protects VICs against in vitro calcification. Here, we hypothesize that the specific interaction of osteopontin with CD44v6, and the related intracellular pathway, prevents calcium deposition in human-derived VICs from patients with aortic valve sclerosis. APPROACH AND RESULTS - On informed consent, 23 patients and 4 controls were enrolled through the cardiac surgery and heart transplant programs. Human aortic valves and VICs were tested for osteogenic transdifferentiation, ex vivo and in vitro. Osteopontin-CD44 interaction was analyzed using proximity ligation assay and the signaling pathways investigated. A murine model based on angiotensin II infusion was used to mimic early pathological remodeling of the aortic valves. We report osteopontin-CD44 functional interaction as a hallmark of early stages of calcific aortic valve disease. We demonstrated that osteopontin-CD44 interaction mediates calcium deposition via phospho-Akt in VICs from patients with noncalcified aortic valve sclerosis. Finally, microdissection analysis of murine valves shows increased cusp thickness in angiotensin II-treated mice versus saline infused along with colocalization of osteopontin and CD44 as seen in human lesions. CONCLUSIONS - Here, we unveil a specific protein-protein association and intracellular signaling mechanisms of osteopontin. Understanding the molecular mechanisms of early VIC activation and calcium deposition in asymptomatic stage of calcific aortic valve disease could open new prospective for diagnosis and therapeutic intervention.",
keywords = "aortic valve, osteopontin",
author = "Paolo Poggio and Emanuela Branchetti and Grau, {Juan B.} and Lai, {Eric K.} and Gorman, {Robert C.} and Gorman, {Joseph H.} and Sacks, {Michael S.} and Bavaria, {Joseph E.} and Giovanni Ferrari",
year = "2014",
doi = "10.1161/ATVBAHA.113.303017",
language = "English",
volume = "34",
pages = "2086--2094",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

TY - JOUR

T1 - Osteopontin-CD44v6 interaction mediates calcium deposition via phospho-akt in valve interstitial cells from patients with noncalcified aortic valve sclerosis

AU - Poggio, Paolo

AU - Branchetti, Emanuela

AU - Grau, Juan B.

AU - Lai, Eric K.

AU - Gorman, Robert C.

AU - Gorman, Joseph H.

AU - Sacks, Michael S.

AU - Bavaria, Joseph E.

AU - Ferrari, Giovanni

PY - 2014

Y1 - 2014

N2 - OBJECTIVE - The activation of valve interstitial cells (VICs) toward an osteogenic phenotype characterizes aortic valve sclerosis, the early asymptomatic phase of calcific aortic valve disease. Osteopontin is a phosphorylated acidic glycoprotein that accumulates within the aortic leaflets and labels VIC activation even in noncalcified asymptomatic patients. Despite this, osteopontin protects VICs against in vitro calcification. Here, we hypothesize that the specific interaction of osteopontin with CD44v6, and the related intracellular pathway, prevents calcium deposition in human-derived VICs from patients with aortic valve sclerosis. APPROACH AND RESULTS - On informed consent, 23 patients and 4 controls were enrolled through the cardiac surgery and heart transplant programs. Human aortic valves and VICs were tested for osteogenic transdifferentiation, ex vivo and in vitro. Osteopontin-CD44 interaction was analyzed using proximity ligation assay and the signaling pathways investigated. A murine model based on angiotensin II infusion was used to mimic early pathological remodeling of the aortic valves. We report osteopontin-CD44 functional interaction as a hallmark of early stages of calcific aortic valve disease. We demonstrated that osteopontin-CD44 interaction mediates calcium deposition via phospho-Akt in VICs from patients with noncalcified aortic valve sclerosis. Finally, microdissection analysis of murine valves shows increased cusp thickness in angiotensin II-treated mice versus saline infused along with colocalization of osteopontin and CD44 as seen in human lesions. CONCLUSIONS - Here, we unveil a specific protein-protein association and intracellular signaling mechanisms of osteopontin. Understanding the molecular mechanisms of early VIC activation and calcium deposition in asymptomatic stage of calcific aortic valve disease could open new prospective for diagnosis and therapeutic intervention.

AB - OBJECTIVE - The activation of valve interstitial cells (VICs) toward an osteogenic phenotype characterizes aortic valve sclerosis, the early asymptomatic phase of calcific aortic valve disease. Osteopontin is a phosphorylated acidic glycoprotein that accumulates within the aortic leaflets and labels VIC activation even in noncalcified asymptomatic patients. Despite this, osteopontin protects VICs against in vitro calcification. Here, we hypothesize that the specific interaction of osteopontin with CD44v6, and the related intracellular pathway, prevents calcium deposition in human-derived VICs from patients with aortic valve sclerosis. APPROACH AND RESULTS - On informed consent, 23 patients and 4 controls were enrolled through the cardiac surgery and heart transplant programs. Human aortic valves and VICs were tested for osteogenic transdifferentiation, ex vivo and in vitro. Osteopontin-CD44 interaction was analyzed using proximity ligation assay and the signaling pathways investigated. A murine model based on angiotensin II infusion was used to mimic early pathological remodeling of the aortic valves. We report osteopontin-CD44 functional interaction as a hallmark of early stages of calcific aortic valve disease. We demonstrated that osteopontin-CD44 interaction mediates calcium deposition via phospho-Akt in VICs from patients with noncalcified aortic valve sclerosis. Finally, microdissection analysis of murine valves shows increased cusp thickness in angiotensin II-treated mice versus saline infused along with colocalization of osteopontin and CD44 as seen in human lesions. CONCLUSIONS - Here, we unveil a specific protein-protein association and intracellular signaling mechanisms of osteopontin. Understanding the molecular mechanisms of early VIC activation and calcium deposition in asymptomatic stage of calcific aortic valve disease could open new prospective for diagnosis and therapeutic intervention.

KW - aortic valve

KW - osteopontin

UR - http://www.scopus.com/inward/record.url?scp=84906939163&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906939163&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.113.303017

DO - 10.1161/ATVBAHA.113.303017

M3 - Article

VL - 34

SP - 2086

EP - 2094

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 9

ER -