Abstract
Apoptosis (type I programmed cell death) of cardiomyocytes is a major process that plays a role in the progression of heart failure. The early response gene IER3 regulates apoptosis in a wide variety of cells and organs. However, its role in heart failure is largely unknown. Here, we investigate the role of IER3 in an inducible heart failure mouse model. Heart failure was induced in a mouse model that imitates a human titin truncation mutation we found in a patient with dilated cardiomyopathy (DCM). Transferase dUTP nick end labeling (TUNEL) and ssDNA stainings showed induction of apoptosis in titin-deficient cardiomyocytes during heart failure development, while IER3 response was dysregulated. Chromatin immunoprecipitation and knock-down experiments revealed that IER3 proteins target the promotors of anti-apoptotic genes and act as an anti-apoptotic factor in cardiomyocytes. Its expression is blunted during heart failure development in a titin-deficient mouse model. Targeting the IER3 pathway to reduce cardiac apoptosis might be an effective therapeutic strategy to combat heart failure.
Highlights
Congestive heart failure is a major health problem in the western world and affects about 5.7 million adults in the United States [1]
The HET animals exhibited significantly more Transferase dUTP nick end labeling (TUNEL)-positive cardiomyocytes compared to the WT mice (8.26% ± 3.6% vs. 3.18% ± 1.8%, p < 0.05, Figure 1A)
Cardiac apoptosis was further examined by Single-stranded DNA (ssDNA) stainings
Summary
Congestive heart failure is a major health problem in the western world and affects about 5.7 million adults in the United States [1]. Dilated cardiomyopathy (DCM), which is characterized by a dilatation of the ventricles and impaired left-ventricular function, represents the most common cause of non-ischemic forms of heart failure [2]. DCM is a very heterogeneous disease; around 50 genes involved in various cellular functions have been linked to familial DCM [3]. Recent high-throughput based studies revealed that mutations in the giant sarcomeric protein titin ( known as connectin) are the predominant genetic cause for DCM and account for 25% of familial forms of DCM [4]. Titin (TTN) is the largest known protein and is mainly expressed in muscular tissue [5]. As a pivotal building block of the sarcomere, TTN contributes to the passive force in muscle, and scaffolds in muscle, and coordinates structural and signaling proteins [6]
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