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.

Translation of upstream open reading frames (uORFs) typically abrogates translation of main (m)ORFs. The molecular mechanism of uORF regulation in cells is not well understood. Here, we data-mined human and mouse heart ribosome profiling analyses and identified a double-stranded RNA (dsRNA) structure within the GATA4 uORF that cooperates with the start codon to augment uORF translation and inhibits mORF translation. A trans-acting RNA helicase DDX3X inhibits the GATA4 uORF-dsRNA activity and modulates the translational balance of uORF and mORF. Antisense oligonucleotides (ASOs) that disrupt this dsRNA structure promote mORF translation, while ASOs that base-pair immediately downstream (i.e., forming a bimolecular double-stranded region) of either the uORF or mORF start codon enhance uORF or mORF translation, respectively. Human cardiomyocytes and mice treated with a uORF-enhancing ASO showed reduced cardiac GATA4 protein levels and increased resistance to cardiomyocyte hypertrophy. We further show the broad utility of uORF-dsRNA- or mORF-targeting ASO to regulate mORF translation for other mRNAs. This work demonstrates that the uORF-dsRNA element regulates the translation of multiple mRNAs as a generalizable translational control mechanism. Moreover, we develop a valuable strategy to alter protein expression and cellular phenotypes by targeting or generating dsRNA downstream of a uORF or mORF start codon.

The prognostic value of lipid profile remains unclear in soft tissue sarcoma. The aim of the present study was to validate the prognostic value of preoperative plasma lipid profile (high density lipoprotein-cholesterol [HDL-C], low density lipoprotein-cholesterol [LDL-C], cholesterol, and triglycerides) levels on disease-free survival (DFS) and overall survival (OS) in soft tissue sarcoma (STS) patients undergoing extensive and radical surgical resection.The preoperative plasma lipid profile levels of 234 STS patients, who were operated on between 2000 with 2010, were retrospectively evaluated. Kaplan-Meier curves and multivariate Cox proportional models were calculated for DFS and OS.In univariate analysis, a decreased HDL-C level was significantly associated with decreased OS (hazard ratio [HR], 3.405; 95% confidence interval (CI), 1.445-8.021, P = 0.005) and remained significant in the multivariate analysis (HR, 5.615; 95% CI, 1.243-25.378, P = 0.025). Patients with HDL-C < 1.475 mmol/L showed a median OS of 71 months. In contrast, patients with HDL-C ≥1.475 mmol/L had a median OS of 101 months. In univariate analysis, a decreased HDL-C level was significantly associated with decreased DFS (HR, 2.085; 95% CI, 1.271-3.422, P = 0.004) and remained significant in the multivariate analysis (HR, 1.808; 95% CI, 1.118-2.924, P = 0.016). Patients with HDL-C <1.475 mmol/L presented with a median DFS of 47 months, whereas patients with HDL-C ≥1.475 mmol/L had a median DFS of 78 months. In univariate analysis and multivariate analyses regarding OS and DFS, there was no significant association between the groups in terms of LDL-C, CHO and TG.Our study investigated the potential prognostic utility of preoperative plasma HDL-C levels as an independent factor in STS patients who had undergone radical surgical resection.

Cardiac physiology and pathology have been extensively explored at the transcriptional level. Still, they are less understood at the translational level, including three major knowledge gaps: pathophysiological impact, molecular mechanisms, and therapeutic implications of translational control in cardiac biology and heart disease. This review aims to provide a summary of the most recent key findings in this emerging field of translational control in heart health and disease, covering the physiological functions, disease pathogenesis, biochemical mechanisms, and development of potential RNA-based, translation-manipulating drugs. Translation of mRNA to protein is the final step in the central dogma for protein synthesis. Translation machinery includes a family of essential “housekeeping” factors and enzymes required for mRNA translation. These translation factors ensure the accurate processing of mRNA to protein according to the genetic code and maintain the optimal quality and quantity of cellular proteins for normal cardiac function. Translation factors also regulate the efficiency, speed, and fidelity of protein production and play a role in cardiac pathological remodeling under stress conditions. This review first introduces the techniques and methods used to study the translational regulation of gene expression in the cardiac system. We then summarize discoveries of a variety of pathophysiological functions and molecular mechanisms of translational control in cardiac health and disease, focusing on two primary symptoms, cardiac hypertrophy and fibrosis. In these sessions, we discuss the translational regulation directed by specific regulatory factors in cardiac physiology and how their genetic mutations, expression dysregulation, or functional alterations contribute to the etiology of heart disease. Notably, translational control exhibits extensive crosstalk with other processes, including transcriptional regulation, mitochondrial metabolism, and sarcomere homeostasis. Furthermore, recent findings have revealed the role of translational regulation in cardiomyocyte proliferation and heart regeneration, providing new approaches for creating regenerative medicine. Because transcript-specific translational regulation of both pathological and protective proteins occurs in heart disease, target-selective translation inhibitors and enhancers can be developed. These inhibitors and enhancers offer valuable insights into novel therapeutic targets and the development of RNA-based drugs for heart disease treatment.

Cardiac physiology and pathology have been extensively explored at the transcriptional level, but are less understood at the translational level. Translation of mRNA to protein is the final step in the central dogma for protein synthesis. Translation machinery includes a family of essential “housekeeping” factors and enzymes required for mRNA translation. These translation factors ensure the accurate processing of mRNA to protein according to the genetic code and maintain the optimal quality and quantity of cellular proteins for normal cardiac function. Translation factors also control the efficiency, speed, and fidelity of protein production and participate in cardiac pathological remodeling under stress conditions. This review summarizes discoveries of the pathophysiological function and molecular mechanism of translational control in cardiac health and disease. Translational control has extensive crosstalk to other processes such as transcriptional regulation, mi-tochondrial metabolism, and sarcomere homeostasis. We discuss the translational regu-lation directed by specific regulatory factors in cardiac physiology and the etiology of heart disease when they undergo genetic mutation, expression dysregulation, or func-tional alteration. Because transcript-specific translational regulation of pathological and protective proteins occurs in heart disease, target-selective translation inhibitors and enhancers can be developed. These inhibitors and enhancers provide valuable insights into novel therapeutic targets and RNA-based drug development for heart disease treatment.