武汉云克隆科技股份有限公司

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

Collectively, our data implicate DM2-related alterations in the secretory profile of EAT in the pathogenesis of diabetes mellitus-related heart disease.

摘要

背景:

心外膜脂肪组织（EAT）的分泌因子与心肌细胞功能障碍的发展有关系。这项研究的目的是评估2型糖尿病患者（DM2）的心外膜脂肪组织分泌情况的改变是否会影响心肌细胞的收缩功能和胰岛素作用。

方法和结果:

分析了用条件性培养基（CM）培养的原代成年大鼠心肌细胞中心肌细胞的收缩功能和胰岛素作用，此条件性培养基是从2型糖尿病患者或非2型糖尿病患者的心外膜脂肪组织活检外植体中生成的。从同一病人皮下和心包脂肪组织活检得到的条件性培养基作为对照组。2型糖尿病患者得到的条件性培养基（心外膜脂肪组织）处理心肌细胞与其他组获得的条件性培养基处理心肌细胞相比，肌节缩短、胞液钙（2+）流动、肌浆内质网ATP酶2a表达量都降低了，以及胰岛素介导的akt-ser473-磷酸化也减少了。对条件性培养基的性能分析显示，相比非2型糖尿病患者的心外膜脂肪组织得到的条件性培养基、其他脂肪来源的条件性培养基，在2型糖尿病患者的心外膜脂肪组织得到的条件性培养基中，activin A，angiopoietin-2和CD14选择性的积累了。因此，2型糖尿病患者的心外膜脂肪组织活检是以CD14阳性单核细胞集群为特点的。此外，SMAD2-磷酸化作用，activin A信号的下游靶标物，在2型糖尿病患者心外膜脂肪组织得到的条件性培养基处理的心肌细胞中增加了，从2型糖尿病患者的心外膜脂肪组织得到的条件性培养基在心肌细胞中的不利影响通过用抗activin A中和抗体预处理细胞得以废除。最后，activin A和angiopoietin-2的重组蛋白减少了心肌细胞收缩功能，但只有activin A能减少肌浆内质网ATP酶2a的表达。

结论:

总的来说，我们的数据暗示了在糖尿病相关的心脏疾病发病机理中，在心外膜脂肪组织分泌情况中2型糖尿病相关的变化。

使用试剂原文信息：Enzyme-linked immunoabsorbent assays were used to quantify the amount of activin A (USCN, Wuhan, China) and angiopoietin-2 (RayBiotech) in CM.