MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol
MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol
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DOI：
10.1161/circresaha.116.309528
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发表时间：
2017-03-03
影响因子：
20.1
通讯作者：
Ono, Koh
中科院分区：
文献类型：
--
作者：
Nishiga, Masataka;Horie, Takahiro;Ono, Koh
理论基础：心力衰竭和动脉粥样硬化有着共同的慢性炎症和纤维化的潜在机制。高度保守的microRNA(MiR)miR-33被认为是动脉粥样硬化的潜在治疗靶点，因为它调节脂质代谢和炎症。目的：探讨miR-33在心力衰竭中的作用。方法与结果：我们首先研究了扩张型心肌病患者心肌组织中miR-33a/b的表达水平。MiR-33a表达增加与血流动力学参数改善有关。为了阐明miR-33在心脏重塑中的作用，我们研究了miR-33基因缺陷(基因敲除[KO])小鼠对压力超负荷的反应。当小鼠遭受横断性主动脉收缩时，野生型左心室miR-33的表达水平显著上调。与野生型相比，野生型和miR-33KO心脏的肥大反应无差异，而心肌纤维化明显减轻。尽管心肌纤维化得到改善，miR-33KO小鼠在横动脉缩窄后表现出收缩功能受损。我们还发现心脏成纤维细胞主要负责miR-33在心脏的表达。MiR-33的缺失损害了心脏成纤维细胞的增殖，这被认为是由脂筏胆固醇含量改变引起的。此外，心脏成纤维细胞特异性miR-33基因缺陷小鼠与系统miR-33KO小鼠一样，也表现出减少由腹主动脉缩窄引起的心脏纤维化。结论：miR-33参与心脏重塑，并保留成纤维细胞中的脂筏胆固醇含量，维持重塑心脏的适应性纤维化反应。
Rationale: Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33, is considered as a potential therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in heart failure remains to be elucidated.Objective: To clarify the role of miR-33 involved in heart failure.Methods and Results: We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction in miR-33-deficient (knockout [KO]) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast-specific miR-33-deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice.Conclusion: Our results demonstrate that miR-33 is involved in cardiac remodeling, and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.