Rosa Mickael, Paris Camille, Sottejeau Yoann, Corseaux Delphine, Robin Emmanuel, Tagzirt Madjid, Juthier Francis, Jashari Ramadan, Rauch Antoine, Vincentelli André, Staels Bart, Van Belle Eric, Susen Sophie, Dupont Annabelle
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.
Acta Diabetol. 2017 Jun;54(6):551-560. doi: 10.1007/s00592-017-0980-3. Epub 2017 Mar 18.
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.
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.
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.
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.
钙化性主动脉瓣疾病（CAVD）影响65岁以上人群的2%至6%，年龄、性别、吸烟、超重、血脂异常、糖尿病均会促使该疾病的发展。CAVD部分是由人瓣膜间质细胞（VICs）向成骨细胞分化导致的。本研究旨在阐明瘦素对VICs成骨细胞表型的影响及其相关信号通路。
本研究纳入了因CAVD接受主动脉瓣置换术的患者（n = 43）。将无CAVD的冠心病（CAD）患者（n = 129）作为对照。
CAVD患者的血清瘦素浓度高于CAD患者（p = 0.002）。在钙化性主动脉瓣中发现了瘦素，钙化区域的瘦素浓度高于非钙化区域（p = 0.01）。对人VICs进行慢性瘦素刺激可增强碱性磷酸酶（ALP）活性以及ALP、骨形态发生蛋白-2（BMP-2）和RUNX2的表达，并降低骨桥蛋白的表达。此外，在瘦素刺激过程中抑制Akt或ERK可降低VIC中骨细胞标志物的表达。
综上所述，这些发现表明瘦素通过以Akt和ERK依赖的方式促进人主动脉VICs向成骨细胞分化，在CAVD的发展中起关键作用。本研究突出了瘦素在CAVD发展中的作用，还需要进一步研究以确定降低循环瘦素水平或阻断瘦素对VICs的作用是否能有效减缓CAVD的进展。
