FAM114A1 influences cardiac pathological remodeling by regulating angiotensin II signaling
Kadiam C. Venkata Subbaiah, … , Wai Hong Wilson Tang, Peng Yao
Kadiam C. Venkata Subbaiah, … , Wai Hong Wilson Tang, Peng Yao
Published June 7, 2022
Citation Information: JCI Insight. 2022;7(13):e152783. https://doi.org/10.1172/jci.insight.152783.
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Research Article Cardiology

FAM114A1 influences cardiac pathological remodeling by regulating angiotensin II signaling

Abstract

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.

Authors

Kadiam C. Venkata Subbaiah, Jiangbin Wu, Wai Hong Wilson Tang, Peng Yao

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Figure 5

FAM114A1 deletion abolishes Ang II–induced cardiac fibroblast proliferation, myofibroblast activation, and migration.

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FAM114A1 deletion abolishes Ang II–induced cardiac fibroblast prolifera...
(A) Fam114a1 mRNA expression in PMCFs and CMs. Gapdh mRNA was used as normalizer. n = 4 for each group. (B) Endogenous FAM114A1 protein expression in PMCFs and CMs detected by Western blot. GAPDH protein was used as a loading control. n = 3 for each group. (C) Ang II treatment (1 μM) induces FAM114A1 mRNA and protein expression in PMCFs. n = 3 for qPCR and n = 100–120 cells per treatment for IF. 18S rRNA was used as normalizer for mRNA measurement. Scale bar: 20 μm. (D) qPCR measurement of mitotic cyclin gene expression in CFs from WT and Fam114a1–/– mice after Ang II treatment. n = 3 for each group. 18S rRNA was used as a normalizer. (E and F) Representative images of IF staining and quantification of normalized intensity of MF activation markers in CFs of WT and Fam114a1–/– mice after vehicle or Ang II treatment. n = 150–200 cells were analyzed for each group. Scale bar: 20 μm. (G) Representative images of migrating CFs from WT and Fam114a1–/– mice after vehicle or Ang II treatment. Quantification of scratch closure after 24 hours was shown. n = 6 biological replicates for each group. Data are presented as mean ± SEM. Statistical significance was confirmed by 2-tailed Student t test for A–C and 2-way ANOVA with Tukey’s multiple-comparison test for D–G. *P < 0.05; **P < 0.01; ***P <0.001.