Zheng Liu1, Ping Ye1, Sihua Wang1, Jie Wu1, Yuan Sun1, Anchen Zhang1, Linyun Ren1, Chao Cheng1, Xiaofan Huang1, Ke Wang1, Peng Deng1, Chuangyan Wu1, Zhang Yue1, Jiahong Xia2. 1. From the Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China (Z.L.); Department of Cardiovascular Surgery (Z.L., J.W., Y.S., A.Z., L.R., C.C., X.H., K.W., P.D., C.W., Z.Y., J.X.) and Department of Thoracic Surgery (S.W.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Department of Cardiovascular Medicine (P.Y.) and Department of Cardiovascular Surgery (J.X.), Central Hospital of Wuhan, Wuhan, China. 2. From the Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China (Z.L.); Department of Cardiovascular Surgery (Z.L., J.W., Y.S., A.Z., L.R., C.C., X.H., K.W., P.D., C.W., Z.Y., J.X.) and Department of Thoracic Surgery (S.W.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Department of Cardiovascular Medicine (P.Y.) and Department of Cardiovascular Surgery (J.X.), Central Hospital of Wuhan, Wuhan, China. jiahong.xia@mail.hust.edu.cn.
Abstract
BACKGROUND: MicroRNAs (miRs) and inflammatory monocytes participate in many cardiac pathophysiological processes including acute myocardial infarction (AMI). Recently, we observed that miR-150 is downregulated in injured mouse plasma after AMI as well as in human infarcted monocytes. However, the precise functional role of miR-150 in response to AMI remains unknown. METHODS AND RESULTS: In a mouse model of AMI and in human subjects with AMI, we found that miR-150 expression was reduced in monocytes. In vitro studies showed that ectopic expression of miR-150 markedly reduced monocyte migration and proinflammatory cytokine production, whereas blockade of miR-150 had opposing effects. In vivo studies showed that overexpression of miR-150 in mice resulted in improved cardiac function, reduced myocardial infarction size, inhibition of apoptosis, and reduced inflammatory Ly-6C(high) monocyte invasion levels after AMI. Wild-type mice transplanted with miR-150 null (-/-) bone marrow cells could reverse this protective effect. Mechanistic studies demonstrated that miR-150 inhibited the expression of chemokine receptor 4 (CXCR4), thereby promoting monocyte migration. CONCLUSIONS: Our findings indicate that miR-150 acts as a critical regulator of monocyte cell migration and production of proinflammatory cytokines, leading to cardioprotective effects against AMI-induced injury. Thus, miR-150 may be a suitable target for therapeutic intervention in the setting of ischemic heart disease.
BACKGROUND: MicroRNAs (miRs) and inflammatory monocytes participate in many cardiac pathophysiological processes including acute myocardial infarction (AMI). Recently, we observed that miR-150 is downregulated in injured mouse plasma after AMI as well as in human infarcted monocytes. However, the precise functional role of miR-150 in response to AMI remains unknown. METHODS AND RESULTS: In a mouse model of AMI and in human subjects with AMI, we found that miR-150 expression was reduced in monocytes. In vitro studies showed that ectopic expression of miR-150 markedly reduced monocyte migration and proinflammatory cytokine production, whereas blockade of miR-150 had opposing effects. In vivo studies showed that overexpression of miR-150 in mice resulted in improved cardiac function, reduced myocardial infarction size, inhibition of apoptosis, and reduced inflammatory Ly-6C(high) monocyte invasion levels after AMI. Wild-type mice transplanted with miR-150 null (-/-) bone marrow cells could reverse this protective effect. Mechanistic studies demonstrated that miR-150 inhibited the expression of chemokine receptor 4 (CXCR4), thereby promoting monocyte migration. CONCLUSIONS: Our findings indicate that miR-150 acts as a critical regulator of monocyte cell migration and production of proinflammatory cytokines, leading to cardioprotective effects against AMI-induced injury. Thus, miR-150 may be a suitable target for therapeutic intervention in the setting of ischemic heart disease.
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