Apoptosis of hematopoietic progenitor-derived adipose tissue-resident macrophages contributes to insulin resistance after myocardial infarction.
Apoptosis of hematopoietic progenitor-derived adipose tissue-resident macrophages contributes to insulin resistance after myocardial infarction.
复制标题
造血祖细胞来源的脂肪组织驻留巨噬细胞的凋亡会导致心肌梗死后的胰岛素抵抗。
DOI：
10.1126/scitranslmed.aaw0638
复制
发表时间：
2020-07-22
影响因子：
17.1
通讯作者：
Dutta P
中科院分区：
文献类型：
--
作者：
Vasamsetti SB;Coppin E;Zhang X;Florentin J;Koul S;Götberg M;Clugston AS;Thoma F;Sembrat J;Bullock GC;Kostka D;St Croix CM;Chattopadhyay A;Rojas M;Mulukutla SR;Dutta P
胰岛素抵抗患者患心肌梗塞（MI）等心血管疾病的风险较高。然而，尚不清楚心肌梗死是否会引发或加重胰岛素抵抗。我们观察到 ST 段抬高型 MI 患者和 MI 小鼠分别具有新发高血糖和胰岛素抵抗的特征。在心肌和骨骼肌损伤的小鼠模型中，我们观察到，由于这些远处器官损伤后的细胞凋亡，内脏脂肪组织（VAT）驻留巨噬细胞的数量减少。 ST 段抬高型心肌梗死后，患者的 VAT 驻留巨噬细胞数量也出现类似的减少，并出现全身胰岛素抵抗。 MI 损伤后 VAT 驻留巨噬细胞的损失导致非糖尿病小鼠出现全身胰岛素抵抗。啮齿动物心肌梗死后死亡的心肌释放危险信号相关蛋白高迁移率族盒 1，并通过 Toll 样受体 4 引发巨噬细胞凋亡。小鼠稳态中的 VAT 驻留巨噬细胞群在转录组学上与大脑、皮肤、肾脏、骨髓、肺和肝脏中的巨噬细胞不同，源自刚出生后的造血祖细胞。从机制上讲，MI小鼠模型中VAT驻留巨噬细胞凋亡和从头胰岛素抵抗与巨噬细胞集落刺激因子和脂联素浓度降低有关。总的来说，这些发现证明了脂肪组织驻留巨噬细胞在感知远端器官损伤和促进 MI 发病机制中的作用，这一作用此前未被认识到。
Patients with insulin resistance have high risk of cardiovascular disease such as myocardial infarction (MI). However, it is not known whether MI can initiate or aggravate insulin resistance. We observed that patients with ST-elevation MI and mice with MI had de novo hyperglycemia and features of insulin resistance, respectively. In mouse models of both myocardial and skeletal muscle injury, we observed that the number of visceral adipose tissue (VAT)–resident macrophages decreased because of apoptosis after these distant organ injuries. Patients displayed a similar decrease in VAT-resident macrophage numbers and developed systemic insulin resistance after ST-elevation MI. Loss of VAT-resident macrophages after MI injury led to systemic insulin resistance in non-diabetic mice. Danger signaling–associated protein high mobility group box 1 was released by the dead myocardium after MI in rodents and triggered macrophage apoptosis via Toll-like receptor 4. The VAT-resident macrophage population in the steady state in mice was transcriptomically distinct from macrophages in the brain, skin, kidney, bone marrow, lungs, and liver and was derived from hematopoietic progenitor cells just after birth. Mechanistically, VAT-resident macrophage apoptosis and de novo insulin resistance in mouse models of MI were linked to diminished concentrations of macrophage colony-stimulating factor and adiponectin. Collectively, these findings demonstrate a previously unappreciated role of adipose tissue–resident macrophages in sensing remote organ injury and promoting MI pathogenesis.