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

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

AimsAortic 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.Methods and resultsHuman 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.ConclusionThis 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.

Original languageEnglish
Pages (from-to)402-410
Number of pages9
JournalCardiovascular Research
Volume98
Issue number3
DOIs
Publication statusPublished - Jun 1 2013

Fingerprint

Sclerosis
Aortic Valve
Aortic Valve Stenosis
Phenotype
Tissue Engineering
Heart Failure
Cell Culture Techniques
Myocardial Infarction
Transplants

Keywords

  • Aortic valve sclerosis
  • Bone morphogenetic protein 4
  • Calcific aortic stenosis
  • Valve interstitial cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Poggio, P., Sainger, R., Branchetti, E., Grau, J. B., Lai, E. K., Gorman, R. C., ... Ferrari, G. (2013). Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis. Cardiovascular Research, 98(3), 402-410. https://doi.org/10.1093/cvr/cvt055

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

In: Cardiovascular Research, Vol. 98, No. 3, 01.06.2013, p. 402-410.

Research output: Contribution to journalArticle

Poggio, P, Sainger, R, Branchetti, E, Grau, JB, Lai, EK, Gorman, RC, Sacks, MS, Parolari, A, Bavaria, JE & Ferrari, G 2013, 'Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis', Cardiovascular Research, vol. 98, no. 3, pp. 402-410. https://doi.org/10.1093/cvr/cvt055
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. / Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis. In: Cardiovascular Research. 2013 ; Vol. 98, No. 3. pp. 402-410.
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AU - Lai, Eric K.

AU - Gorman, Robert C.

AU - Sacks, Michael S.

AU - Parolari, Alessandro

AU - Bavaria, Joseph E.

AU - Ferrari, Giovanni

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N2 - AimsAortic 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.Methods and resultsHuman 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.ConclusionThis 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.

AB - AimsAortic 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.Methods and resultsHuman 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.ConclusionThis 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.

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KW - Bone morphogenetic protein 4

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