Leptin induces osteoblast differentiation of human valvular interstitial cells via the Akt and ERK pathways.
OBJECTIVE
Calcific aortic valve disease (CAVD) affects 2-6% of the population over 65 years, and age, gender, smoking, overweight, dyslipidemia, diabetes contribute to the development of this disease. CAVD results, in part, from the osteoblast differentiation of human valvular interstitial cells (VICs). This study aims to elucidate the effects of leptin on osteoblast phenotype of VICs and the signalling pathways involved.


METHODS
Patients who underwent aortic valve replacement for CAVD (n = 43) were included in this study. Patients with coronary artery disease (CAD) without CAVD (n = 129) were used as controls.


RESULTS
Patients with CAVD had higher serum leptin concentrations than CAD patients (p = 0.002). Leptin was found in calcific aortic valves, with higher concentrations in calcified versus non-calcified zones (p = 0.01). Chronic leptin stimulation of human VICs enhanced alkaline phosphatase (ALP) activity and ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. Moreover, inhibiting Akt or ERK during leptin stimulation lowered the expression of osteoblast markers in VIC.


CONCLUSIONS
Taken together, these findings indicate that leptin plays a critical role in CAVD development by promoting osteoblast differentiation of human aortic VICs in an Akt- and ERK-dependent manner. This study highlights the role of leptin in CAVD development, and further studies are needed to determine whether reducing circulating leptin levels or blocking leptin actions on VICs is efficient to slow CAVD progression.
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.
Mickael
M
Rosa
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.|Cardiovascular and Pulmonary and Haematology Department, CHRU de Lille, Lille, France.
Camille
C
Paris
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.
Yoann
Y
Sottejeau
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.
Delphine
D
Corseaux
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.|Cardiovascular and Pulmonary and Haematology Department, CHRU de Lille, Lille, France.
Emmanuel
E
Robin
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.
Madjid
M
Tagzirt
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.|Cardiovascular and Pulmonary and Haematology Department, CHRU de Lille, Lille, France.
Francis
F
Juthier
European Homograft Bank, c/o Clinique Saint Jean, Brussels, Belgium.
Ramadan
R
Jashari
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.|Cardiovascular and Pulmonary and Haematology Department, CHRU de Lille, Lille, France.
Antoine
A
Rauch
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.
André
A
Vincentelli
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.
Bart
B
Staels
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.|Cardiovascular and Pulmonary and Haematology Department, CHRU de Lille, Lille, France.
Eric
E
Van Belle
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France. sophiesusen@aol.com.|Institut Pasteur de Lille, 59000, Lille, France. sophiesusen@aol.com.|Cardiovascular and Pulmonary and Haematology Department, CHRU de Lille, Lille, France. sophiesusen@aol.com.|INSERM U 1011, Amphi J&K, Boulevard du Professeur Jules Leclercq, 59008, Lille Cedex, France. sophiesusen@aol.com.
Sophie
S
Susen
European Genomic Institute for Diabetes (E.G.I.D.), FR 3508, UNIV LILLE, Inserm UMR 1011, 59000, Lille, France.|Institut Pasteur de Lille, 59000, Lille, France.|Cardiovascular and Pulmonary and Haematology Department, CHRU de Lille, Lille, France.
Annabelle
A
Dupont
D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000187:drug effects* / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D015415:Biomarkers / Q000378:metabolism; D002114:Calcinosis / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects*; D054338:Cell Transdifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D006330:Heart Defects, Congenital / Q000473:pathology; D006349:Heart Valve Diseases / Q000473:pathology; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000502:physiology*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects
D015415:Biomarkers; D020738:Leptin; D051058:Oncogene Protein v-akt
Calcific aortic valve disease; Human valvular interstitial cells; Leptin; Osteoblast differentiation