Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Worker's Stadium South Road, Beijing 100020, China.
Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, No.193, Lianhe Road, Xigang District, Dalian 116011, China.
J Adv Res. 2024 Jan;55:17-31. doi: 10.1016/j.jare.2023.02.010. Epub 2023 Feb 21.
Leukocyte infiltration is an early event during cardiac remodeling frequently leading to heart failure (HF). Integrins mediate leukocyte infiltration during inflammation. However, the importance of specific integrins in hypertensive cardiac remodeling is still unclear.
To elucidate the significance of CD11b in hypertensive cardiac remodeling.
Angiotensin (Ang II) or deoxycorticosterone acetate (DOCA)-salt was used to induce cardiac remodeling in mice of gene knockout (KO), bone marrow (BM) chimera, and the CD11b neutralizing antibody or agonist leukadherin-1 (LA1) treatment.
Our microarray data showed that integrin subunits Itgam (CD11b) and Itgb2 (CD18) were the most highly upregulated in Ang II-infused hearts. CD11b expression and CD11b/CD18 myelomonocytes were also time-dependently increased. KO or pharmacological blockade of CD11b greatly attenuated cardiac remodeling and macrophage infiltration and M1 polarization induced by Ang II or DOCA-salt. This protection was verified in wild-type mice transplanted with CD11b-deficient BM cells. Conversely, administration of CD11b agonist LA1 showed the opposite effects. Further, CD11b KO reduced Ang II-induced macrophage adhesion and M1 polarization, leading to reduction of cardiomyocyte enlargement and fibroblast differentiation in vitro. The numbers of CD14CD11bCD18 monocytes and CD15CD11bCD18 granulocytes were obviously higher in HF patients than in normal controls.
Our data demonstrate an important role of CD11b myeloid cells in hypertensive cardiac remodeling, and suggest that HF may benefit from targeting CD11b.
白细胞浸润是心脏重构的早期事件，常导致心力衰竭（HF）。整合素在炎症期间介导白细胞浸润。然而，特定整合素在高血压性心脏重构中的重要性仍不清楚。
阐明 CD11b 在高血压性心脏重构中的意义。
血管紧张素（Ang II）或去氧皮质酮醋酸盐（DOCA-盐）用于诱导基因敲除（KO）、骨髓（BM）嵌合体小鼠的心脏重构，以及 CD11b 中和抗体或激动剂 leukadherin-1（LA1）治疗。
我们的微阵列数据显示，整合素亚基 Itgam（CD11b）和 Itgb2（CD18）在 Ang II 输注心脏中表达上调最为明显。CD11b 表达和 CD11b/CD18 髓样细胞也呈时间依赖性增加。KO 或 CD11b 的药理学阻断极大地减弱了 Ang II 或 DOCA-盐诱导的心脏重构和巨噬细胞浸润以及 M1 极化。在接受 CD11b 缺陷型 BM 细胞移植的野生型小鼠中验证了这种保护作用。相反，给予 CD11b 激动剂 LA1 则显示出相反的效果。此外，CD11b KO 减少了 Ang II 诱导的巨噬细胞黏附和 M1 极化，导致体外心肌细胞增大和成纤维细胞分化减少。HF 患者的 CD14CD11bCD18 单核细胞和 CD15CD11bCD18 粒细胞数量明显高于正常对照。
我们的数据表明 CD11b 髓样细胞在高血压性心脏重构中具有重要作用，并表明 HF 可能受益于靶向 CD11b。
