Abstract
Ischemic cardiomyopathy (ICM) represents a worldwide health issue owning to its high sudden death rate. Easy diagnosis and effective treatment of ICM are still lacking. Identification of novel molecular markers will help illustrate the pathophysiology of ICM and facilitate its diagnosis and targeted treatment. Transcription profiling could be an easy and efficient way for identifying new markers. However, the mega data in the available database may contain a large number of false-positive hits. To identify the true marker for ICM, we systematically compared available microarray datasets in the GEO database and identified 26 genes that are shared by all datasets. We further verified the expression pattern of these 26 genes in ICM rat model. Only 12 genes show significant differential expression in our animal model. Among them, we focused on PHLDA1, a well-documented pro-apoptotic factor. Expression of PHLDA1 was elevated in both ischemic cardiac cell lines and in rat model. Overexpression of PHLDA1 promotes apoptosis of cardiac muscle cell. Meanwhile, PHLDA1 not only inhibited AKT pathway, but also activated p53 pathway. We thus confirmed PHLDA1 as a true molecular marker for ICM.
Highlights
Ischemic cardiomyopathy (ICM) is the leading cause of sudden cardiac death worldwide (Candell-Riera et al 2009)
The results showed that PHLDA1 protein level was increased significantly after the surgery, as indicated by the increasing brown color in the staining (Fig. 2a) and elevated expression level in western blot assay (Fig. 2b)
We searched through Gene Expression Omnibus (GEO) database and found four datasets that were associated with human ICM samples (Table S1 — see Electronic Supplementary Material) (Kittleson et al 2005; Gronich et al 2010; Kong et al 2010; Hannenhalli et al 2006)
Summary
Ischemic cardiomyopathy (ICM) is the leading cause of sudden cardiac death worldwide (Candell-Riera et al 2009). Previous studies have revealed that multiple molecular signaling pathways in cardiac hypertrophy, inflammatory signaling, oxidative stress, and calcium signaling contribute to ICM (Feldman et al 2005; Wehrens and Marks 2004; Yano et al 2005). Stress-induced apoptosis is responsible for sustained cardiac cell death, cardiac dysfunction and heart failure (Fliss and Gattinger 1996; Foo et al 2005). ICM therapies targeting the apoptosis pathway have been widely explored. Inhibitors targeting apoptotic signaling β-adrenergic receptor are commonly used in heart failure therapy (Nussinovitch and Shoenfeld 2013). Broad-spectrum caspase inhibitors have been shown to prevent dilation, attenuate cardiac dysfunction and reduce heart failure in transgenic mice (Wencker et al 2003; Hayakawa et al 2003; Chandrashekhar et al 2004). Proteins involved in apoptosis signaling could be potential therapeutic targets or diagnosis markers for ICM
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