Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.
Circulation. 2012 Nov 6;126(19):2324-34. doi: 10.1161/CIRCULATIONAHA.111.039586. Epub 2012 Oct 12.
Secreted factors from epicardial adipose tissue (EAT) have been implicated in the development of cardiomyocyte dysfunction. This study aimed to assess whether alterations in the secretory profile of EAT in patients with type 2 diabetes mellitus (DM2) affect contractile function and insulin action in cardiomyocytes.
Contractile function and insulin action were analyzed in primary adult rat cardiomyocytes incubated with conditioned media (CM) generated from explants of EAT biopsies obtained from patients without and with DM2. CM from subcutaneous and pericardial adipose tissue biopsies from the same patients served as the control. Cardiomyocytes treated with CM (EAT) from DM2 patients showed reductions in sarcomere shortening, cytosolic Ca(2+) fluxes, expression of sarcoplasmic endoplasmic reticulum ATPase 2a, and decreased insulin-mediated Akt-Ser473-phosphorylation as compared with CM from the other groups. Profiling of the CM showed that activin A, angiopoietin-2, and CD14 selectively accumulated in CM-EAT-DM2 versus CM-EAT in patients without DM2 and CM from the other fat depots. Accordingly, EAT biopsies from DM2 patients were characterized by clusters of CD14-positive monocytes. Furthermore, SMAD2-phosphorylation, a downstream target of activin A signaling, was elevated in cardiomyocytes treated with CM (EAT) from DM2 patients, and the detrimental effects of CM (EAT) from DM2 patients were partially abolished in cardiomyocytes pretreated with a neutralizing antibody against activin A. Finally, both recombinant activin A and angiopoietin-2 reduced cardiomyocyte contractile function, but only activin A reduced the expression of sarcoplasmic endoplasmic reticulum ATPase 2a.
Collectively, our data implicate DM2-related alterations in the secretory profile of EAT in the pathogenesis of diabetes mellitus-related heart disease.
心外膜脂肪组织 (EAT) 分泌的因子与心肌细胞功能障碍的发展有关。本研究旨在评估 2 型糖尿病 (DM2) 患者 EAT 分泌谱的改变是否影响心肌细胞的收缩功能和胰岛素作用。
用来自无 DM2 和 DM2 患者的 EAT 活检标本的条件培养基 (CM) 孵育原代成年大鼠心肌细胞，分析收缩功能和胰岛素作用。来自同一患者的皮下和心包脂肪组织活检的 CM 作为对照。与其他组相比，用来自 DM2 患者的 CM (EAT) 处理的心肌细胞显示肌节缩短、胞质 Ca(2+) 流、肌浆内质网 ATP 酶 2a 的表达减少以及胰岛素介导的 Akt-Ser473 磷酸化减少。CM 的分析表明，激活素 A、血管生成素-2 和 CD14 选择性地在 CM-EAT-DM2 中积累，而不是在无 DM2 患者的 CM-EAT 中和其他脂肪组织中的 CM 中。因此，DM2 患者的 EAT 活检表现为 CD14 阳性单核细胞簇。此外，用来自 DM2 患者的 CM (EAT) 处理的心肌细胞中 SMAD2 磷酸化增加，这是激活素 A 信号通路的下游靶标，用激活素 A 的中和抗体预处理心肌细胞可部分消除来自 DM2 患者的 CM (EAT) 的有害作用。最后，重组激活素 A 和血管生成素-2 均可降低心肌细胞的收缩功能，但只有激活素 A 降低肌浆内质网 ATP 酶 2a 的表达。
总之，我们的数据表明，DM2 相关的 EAT 分泌谱改变参与了糖尿病相关心脏病的发病机制。
