Relaxin Family Member Insulin-Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models.
Relaxin Family Member Insulin-Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models.
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DOI：
10.1161/jaha.117.008441
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发表时间：
2018-06-10
影响因子：
5.4
通讯作者：
Walsh K
中科院分区：
文献类型：
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作者：
Maruyama S;Wu CL;Yoshida S;Zhang D;Li PH;Wu F;Parker Duffen J;Yao R;Jardin B;Adham IM;Law R;Berger J;Di Marchi R;Walsh K
胰岛素/胰岛素样生长因子/松弛素家族代表一组结构相关但功能不同的蛋白质。家族成员松弛素-2已在临床试验中评估其治疗急性心力衰竭的疗效。在这项研究中，我们评估了胰岛素样肽6（INSL 6），该蛋白质家族的另一个成员，在小鼠心力衰竭模型中的作用，使用遗传功能丧失和蛋白质递送方法。Insl 6缺陷型和野生型（C57 BL/6 N）小鼠分别通过渗透泵连续输注或腹膜内注射给予血管紧张素II或异丙肾上腺素，每天一次，持续2周。在两种模型中，Insl 6敲除小鼠表现出更大的心脏收缩功能障碍和左心室扩张。Insl 6敲除小鼠的心功能障碍与更广泛的心脏纤维化和纤维化相关基因的更高表达相关。持续输注化学合成的INSL 6显著减轻由异丙肾上腺素输注诱导的左心室收缩功能障碍和心脏纤维化。基因表达谱表明，在用INSL 6蛋白处理的异丙肾上腺素激发的心脏中，肝脏X受体/维甲酸X受体信号传导被激活。内源性Insl 6蛋白抑制血管紧张素II和异丙肾上腺素诱导的心脏应激模型中的心脏收缩功能障碍和心脏纤维化。施用重组INSL 6蛋白可用于治疗心力衰竭和心脏纤维化。
The insulin/insulin‐like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin‐2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin‐like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss‐of‐function and protein delivery methods. Insl6‐deficient and wild‐type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks. In both models, Insl6‐knockout mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation. Cardiac dysfunction in the Insl6‐knockout mice was associated with more extensive cardiac fibrosis and greater expression of fibrosis‐associated genes. The continuous infusion of chemically synthesized INSL6 significantly attenuated left ventricular systolic dysfunction and cardiac fibrosis induced by isoproterenol infusion. Gene expression profiling suggests liver X receptor/retinoid X receptor signaling is activated in the isoproterenol‐challenged hearts treated with INSL6 protein. Endogenous Insl6 protein inhibits cardiac systolic dysfunction and cardiac fibrosis in angiotensin II– and isoproterenol‐induced cardiac stress models. The administration of recombinant INSL6 protein could have utility for the treatment of heart failure and cardiac fibrosis.