Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction.
Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction.
复制标题
DOI：
10.1161/circresaha.116.308688
复制
发表时间：
2016-06-10
影响因子：
20.1
通讯作者：
Dawn B
中科院分区：
文献类型：
--
作者：
Zhao L;Cheng G;Jin R;Afzal MR;Samanta A;Xuan YT;Girgis M;Elias HK;Zhu Y;Davani A;Yang Y;Chen X;Ye S;Wang OL;Chen L;Hauptman J;Vincent RJ;Dawn B
白细胞介素（IL）-6在心肌细胞肥大发病机制中的作用仍存在争议。最终确定IL-6信号传导是否是压力超负荷诱导的左心室（LV）肥大的发展所必需的，并阐明潜在的分子途径。野生型（WT）和IL-6敲除（IL-6−/−）小鼠接受假手术或横向主动脉缩窄（TAC）以诱导压力超负荷。系列超声心动图和终末血流动力学研究显示，TAC后IL-6−/−小鼠的LV肥大减弱，LV功能保持上级。TAC后IL-6−/−心脏的LV重塑、纤维化和凋亡程度降低。心肌组织的转录和蛋白质分析确定CaMKII和STAT 3激活为TAC诱导的心肌肥大过程中的重要潜在机制。在暴露于促肥大剂的WT和IL-6−/−小鼠的分离心肌细胞中证实了这些途径参与肌细胞肥大。此外，H9 c2细胞中CaMKII的过表达增加了STAT 3磷酸化，并且H9 c2细胞暴露于IL-6导致STAT 3活化，其通过CaMKII抑制而减弱。这些结果共同确定了心肌细胞肥大期间通过IL-6信号传导的STAT 3的CaMK II依赖性激活的重要性。IL-6的基因缺失可减弱TAC诱导的LV肥大和功能障碍，表明IL-6在响应压力超负荷的LV肥大的发病机制中起关键作用。CaMKII在IL-6诱导的STAT 3激活和随后的心肌细胞肥大中起重要作用。这些发现可能对高血压患者的左室肥厚和衰竭具有重要的治疗意义。
The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy, and to elucidate the underlying molecular pathways. Wild-type (WT) and IL-6 knockout (IL-6−/−) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6−/− mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6−/− hearts after TAC. Transcriptional and protein assays of myocardial tissue identified CaMKII and STAT3 activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from WT and IL-6−/− mice exposed to pro-hypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension.