Paracrine signal emanating from stressed cardiomyocytes aggravates inflammatory microenvironment in diabetic cardiomyopathy.
Paracrine signal emanating from stressed cardiomyocytes aggravates inflammatory microenvironment in diabetic cardiomyopathy.
复制标题
应激心肌细胞旁分泌信号改变糖尿病心肌病炎症微环境。
DOI：
10.1016/j.isci.2022.103973
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发表时间：
2022-03-18
期刊：
影响因子：
5.8
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Kaur N;Ruiz-Velasco A;Raja R;Howell G;Miller JM;Abouleisa RRE;Ou Q;Mace K;Hille SS;Frey N;Binder P;Smith CP;Fachim H;Soran H;Swanton E;Mohamed TMA;Müller OJ;Wang X;Chernoff J;Cartwright EJ;Liu W
心肌炎症通过不完全明确的潜在机制导致糖尿病患者心肌病。在人类和时间过程的实验样本中，糖尿病心脏表现出异常的ER，在啮齿动物中随着时间的推移发生了不适应的变化。此外，作为心脏内质网功能障碍模型，心脏特异性p21活化激酶2 （PAK2）缺失的小鼠在糖尿病中表现出更高的心肌炎症反应。机制上，适应性不良内质网应激诱导的CCAAT/增强子结合蛋白同源蛋白（CHOP）是心脏高迁移率组盒-1 （HMGB1）的一种新型转录调节因子。心脏应激诱导的HMGB1释放促进M1巨噬细胞极化，加重心肌炎症。在治疗上，使用甘草酸隔离细胞外HMGB1通过其抗炎作用赋予心脏保护作用。我们的研究结果还表明，完整的心脏内质网功能和抗糖尿病药物的保护作用相互依赖地减轻了心脏炎症诱导的功能障碍。总的来说，我们引入了内质网应激介导的心肌细胞-巨噬细胞联系，改变了巨噬细胞反应，从而为糖尿病相关心功能障碍的治疗前景提供了见解。
Myocardial inflammation contributes to cardiomyopathy in diabetic patients through incompletely defined underlying mechanisms. In both human and time-course experimental samples, diabetic hearts exhibited abnormal ER, with a maladaptive shift over time in rodents. Furthermore, as a cardiac ER dysfunction model, mice with cardiac-specific p21-activated kinase 2 (PAK2) deletion exhibited heightened myocardial inflammatory response in diabetes. Mechanistically, maladaptive ER stress-induced CCAAT/enhancer-binding protein homologous protein (CHOP) is a novel transcriptional regulator of cardiac high-mobility group box-1 (HMGB1). Cardiac stress-induced release of HMGB1 facilitates M1 macrophage polarization, aggravating myocardial inflammation. Therapeutically, sequestering the extracellular HMGB1 using glycyrrhizin conferred cardioprotection through its anti-inflammatory action. Our findings also indicated that an intact cardiac ER function and protective effects of the antidiabetic drug interdependently attenuated the cardiac inflammation-induced dysfunction. Collectively, we introduce an ER stress-mediated cardiomyocyte-macrophage link, altering the macrophage response, thereby providing insight into therapeutic prospects for diabetes-associated cardiac dysfunction. In response to metabolic stress, loss of cardiac PAK2 leads to maladaptive ER stress Cardiac CHOP-upregulated HMGB1 promotes M1 macrophage polarization by paracrine action Pharmacological inhibition of HMGB1 decelerates myocardial inflammation Vildagliptin and remediated ER alleviate cardiac dysfunction in diabetes Cardiovascular medicine; Biological sciences; Immunology; Cell biology
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影响因子：
6
作者：
Andersson U;Tracey KJ;Yang H
通讯作者：
Yang H
白细胞在糖尿病心肌病中的作用。
影响因子：
4
作者：
Bajpai A;Tilley DG
通讯作者：
Tilley DG
影响因子：
2
作者：
Gotoh T;Endo M;Oike Y
通讯作者：
Oike Y
影响因子：
4.6
作者：
Isfort, Michael;Stevens, Sarah C. W.;Schaffer, Stephen;Jong, Chian Ju;Wold, Loren E.
通讯作者：
Wold, Loren E.
影响因子：
37.8
作者：
Edgar L;Akbar N;Braithwaite AT;Krausgruber T;Gallart-Ayala H;Bailey J;Corbin AL;Khoyratty TE;Chai JT;Alkhalil M;Rendeiro AF;Ziberna K;Arya R;Cahill TJ;Bock C;Laurencikiene J;Crabtree MJ;Lemieux ME;Riksen NP;Netea MG;Wheelock CE;Channon KM;Rydén M;Udalova IA;Carnicer R;Choudhury RP
通讯作者：
Choudhury RP