FAM114A1 influences cardiac pathological remodeling by regulating angiotensin II signaling.
FAM114A1 influences cardiac pathological remodeling by regulating angiotensin II signaling.
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DOI：
10.1172/jci.insight.152783
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发表时间：
2022-07-08
期刊：
影响因子：
8
通讯作者：
Yao, Peng
中科院分区：
文献类型：
--
作者：
Subbaiah, Kadiam C. Venkata;Wu, Jiangbin;Tang, Wai Hong Wilson;Yao, Peng
心脏病理性重构是心力衰竭（HF）和死亡的主要原因，是HF治疗的重要靶点。然而，控制心脏重塑的信号通路尚未完全阐明。在这里，我们发现，一个功能未注释的人类心肌梗死相关（MI相关）基因，家庭与序列相似性114成员A1（FAM 114 A1），是诱导失败的人类和小鼠心脏相比，非衰竭的心脏。小鼠基因组中Fam 114 a1的纯合KO（Fam 114 a1-/-）减少心肌细胞肥大、炎症和心脏纤维化，同时恢复血管紧张素II诱导的（Ang II诱导的）和MI诱导的HF小鼠模型中的心脏功能。心脏成纤维细胞（CF）在不同的心脏细胞类型中表现出最高的FAM 114 A1表达。FAM 114 A1是CF增殖、活化和迁移的关键自主因子。FAM 114 A1与血管紧张素受体相关蛋白（AGTRAP）相互作用，调节血管紧张素1型受体（AT 1 R）的表达和下游血管紧张素II信号转导，进而影响促纤维化反应。我们的研究结果表明，FAM 114 A1调节血管紧张素II信号，从而激活CF和其他心脏细胞，并增强病理性心脏重塑。这些发现为心脏重塑的调节提供了潜在的新见解，并将FAM 114 A1确定为治疗心脏病的治疗靶点。
Cardiac pathological remodeling, a primary contributor to heart failure (HF) and death, is an important target for HF therapy. However, the signaling pathways that govern cardiac remodeling are not fully elucidated. Here, we found that a functionally unannotated human myocardial infarction–associated (MI-associated) gene, family with sequence similarity 114 member A1 (FAM114A1), is induced in failing human and mouse hearts compared with nonfailing hearts. Homozygous KO of Fam114a1 (Fam114a1–/–) in the mouse genome reduces cardiomyocyte hypertrophy, inflammation, and cardiac fibrosis while restoring cardiac function in angiotensin II–induced (Ang II–induced) and MI-induced HF mouse models. Cardiac fibroblasts (CFs) exhibit the highest FAM114A1 expression among different cardiac cell types. FAM114A1 is a critical autonomous factor for CF proliferation, activation, and migration. Mechanistically, FAM114A1 interacts with angiotensin receptor–associated protein (AGTRAP) and regulates the expression of angiotensin type 1 receptor (AT1R) and downstream Ang II signaling transduction, and it subsequently influences profibrotic response. Our results indicate that FAM114A1 regulates Ang II signaling, thereby activating CFs and other cardiac cells and augmenting pathological cardiac remodeling. These findings provide potentially novel insights into the regulation of cardiac remodeling and identify FAM114A1 as a therapeutic target for the treatment of heart disease.
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