Hao Yan, Chen Lianghua, Jiang Zhilong
Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China.
Department of Pulmonary Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, P.R. China.
Exp Ther Med. 2022 May;23(5):350. doi: 10.3892/etm.2022.11277. Epub 2022 Mar 24.
Cluster of differentiation 47 (CD47) is upregulated in mouse models of doxorubicin (Dox)-induced dilated cardiomyopathy (DCM). To explore the role of CD47 in the development of DCM, in the present study, CD47 signaling was blocked by an anti-CD47 neutralizing antibody (aCD47) in mice with Dox-induced DCM. Intraperitoneal (i.p.) administration of 10 mg/kg Dox once a week significantly induced the development of DCM after 4 weeks, which was accompanied by the upregulation of CD47 expression in heart tissues. However, co-administration of Dox with 7 mg/kg aCD47 once a week significantly reduced the severity of DCM, with lower numbers of disordered and broken myofibers, reduced cardiomyocytes and infiltration of macrophages in the heart tissues of treated mice. The beneficial effects were associated with the reduced population of Annexin V7-AAD apoptotic cells, and the attenuated formation of interstitial fibrosis and release of lactate dehydrogenase (LDH) in the aCD47-treated mice. In addition, co-administration with aCD47 effectively reduced the expression of Bax, collagen I, interleukin (IL)-6 and tumor necrosis factor (TNF)-α in murine DCM. These results were further supported by an study, in which aCD47 pre-treatment significantly reduced the Dox-induced early apoptosis of cardiomyocytes and suppressed the expression of Bax, cleaved caspase-1/3 and phosphorylation of p38 MAPK. Therefore, aCD47 attenuated DCM in mice, possibly by suppressing cardiomyocyte early apoptosis and p38 MAPK signaling. CD47 may be a useful therapeutic target in the treatment of DCM.
分化簇47（CD47）在阿霉素（Dox）诱导的扩张型心肌病（DCM）小鼠模型中表达上调。为了探究CD47在DCM发生发展中的作用，在本研究中，用抗CD47中和抗体（aCD47）阻断Dox诱导的DCM小鼠的CD47信号通路。每周一次腹腔注射10 mg/kg Dox，4周后显著诱导DCM的发生，同时伴有心脏组织中CD47表达上调。然而，每周一次将Dox与7 mg/kg aCD47联合给药可显著减轻DCM的严重程度，治疗小鼠心脏组织中肌纤维紊乱和断裂的数量减少，心肌细胞减少，巨噬细胞浸润减少。这些有益作用与aCD47治疗小鼠中膜联蛋白V⁺7-AAD凋亡细胞数量减少、间质纤维化形成减轻以及乳酸脱氢酶（LDH）释放减少有关。此外，与aCD47联合给药可有效降低小鼠DCM中Bax、I型胶原、白细胞介素（IL）-6和肿瘤坏死因子（TNF）-α的表达。另一项研究进一步支持了这些结果，其中aCD47预处理显著减少了Dox诱导的心肌细胞早期凋亡，并抑制了Bax、裂解的半胱天冬酶-1/3的表达以及p38丝裂原活化蛋白激酶（p38 MAPK）的磷酸化。因此，aCD47可能通过抑制心肌细胞早期凋亡和p38 MAPK信号通路减轻小鼠DCM。CD47可能是治疗DCM的一个有用的治疗靶点。
