MicroRNA‐574 regulates FAM210A expression and influences pathological cardiac remodeling

Abstract

Aberrant expression of mitochondrial proteins impairs cardiac function and causes heart disease. The mechanism of regulation of mitochondria encoded protein expression during cardiac disease, however, remains underexplored. Here, we show that multiple pathogenic cardiac stressors induce the expression of miR‐574 guide and passenger strands (miR‐574‐5p/3p) in both humans and mice. miR‐574 knockout mice exhibit severe cardiac disorder under different pathogenic cardiac stresses while miR‐574‐5p/3p mimics that are delivered systematically using nanoparticles reduce cardiac pathogenesis under disease insults. Transcriptomic analysis of miR‐574‐null hearts uncovers family with sequence similarity 210 member A (FAM210A) as a common target mRNA of miR‐574‐5p and miR‐574‐3p. The interactome capture analysis suggests that FAM210A interacts with mitochondrial translation elongation factor EF‐Tu. Manipulating miR‐574‐5p/3p or FAM210A expression changes the protein expression of mitochondrial‐encoded electron transport chain (ETC) genes but not nuclear‐encoded mitochondrial ETC genes in both human AC16 cardiomyocyte cells and miR‐574‐null murine hearts. Together, we discovered that miR‐574 regulates FAM210A expression and modulates mitochondrial‐encoded protein expression, which may influence cardiac remodeling in heart failure.

FAM114A1 Influences Cardiac Fibrosis by Regulating Angiotensin II Signaling in Cardiac Fibroblasts

“…Both the host gene FAM114A1 and miR-574 expression is correlated (32). Thus, it is expected that FAM114A1 mRNA is induced in human and mouse MI and even aged murine hearts together with miR-574 (28)(29)(30)(31)(32). We have confirmed that FAM114A1 mRNA and protein expression is induced in human and mouse failing hearts compared to healthy hearts, especially in the activated MFs (Figure 1 and S1).…”

“…FAM114A1 is a host gene for miR-574 and shares the common promoter with embedded intronic miR-574 (31, 32). Both the host gene FAM114A1 and miR-574 expression is correlated (32).…”

“…We have confirmed that FAM114A1 mRNA and protein expression is induced in human and mouse failing hearts compared to healthy hearts, especially in the activated MFs (Figure 1 and S1). We previously observed induced miR-574-3p in activated CFs in WT mice upon the transverse aortic constriction (TAC) surgery (31). These results suggest that the host gene FAM114A1 and embedded intronic miR-574-3p are coordinated in their expression.…”

“…These results suggest that the host gene FAM114A1 and embedded intronic miR-574-3p are coordinated in their expression. Intriguingly, miR-574-3p plays a role in antagonizing TGF- β -induced CF activation in primary cell culture as well as in TAC mouse model via nanoparticle delivery (31). Here, we show that the host gene FAM114A1 contributes to enhanced Ang II signaling and pro-fibrotic response, implying an antagonistic function relationship between the host gene and embedded miRNA.…”

“…These genetic associations of FAM114A1 gene with MI and CAD imply its potential impact in cardiac pathogenesis. From data mining of high throughput screen for upregulated miRNAs in cardiac pathogenesis, we identified miR-574 as a miRNA that is consistently induced in the human and mouse heart in response to pathological cardiac remodeling (28)(29)(30)(31). The host gene of miR-574, FAM114A1, has been shown to be co-expressed with the embedded intronic miRNA in the brain (32).…”