Abstract
Background:Mature cardiomyocytes are unable to proliferate, preventing the injured adult heart from repairing itself. Studies in rodents have suggested that the extracellular matrix protein agrin promotes cardiomyocyte proliferation in the developing heart and that agrin expression is downregulated shortly after birth, resulting in the cessation of proliferation. Agrin based therapies have proven successful at inducing repair in animal models of cardiac injury, however whether similar pathways exist in the human heart is unknown.MethodsRight ventricular (RV) biopsies were collected from 40 patients undergoing surgery for congenital heart disease and the expression of agrin and associated proteins was investigated.ResultsAgrin transcripts were found in all samples and their levels were significantly negatively correlated to age (p = 0.026), as were laminin transcripts (p = 0.023), whereas no such correlation was found for the other proteins analyzed. No significant correlations for any of the proteins were found when grouping patients by their gender or pathology. Immunohistochemistry and western blots to detect and localize agrin and the other proteins under analysis in RV tissue, confirmed their presence in patients of all ages.ConclusionsWe show that agrin is progressively downregulated with age in human RV tissue but not as dramatically as has been demonstrated in mice; highlighting both similarities and differences to findings in rodents. Our results lay the groundwork for future studies exploring the potential of agrin-based therapies in the repair of damaged human hearts.
Highlights
One major challenge in cardiovascular medicine is the loss of proliferative capacity of mammalian cardiomyocytes shortly after birth, rendering the adult heart unable to repair itself following an injury such as a myocardial infarction [1, 2]
Using a mouse model they found that the expression of agrin, a protein known to play a vital role in cardiac development [4, 5], is highest in the first days of postnatal life and significantly downregulated by day 7, which would exactly correspond to the timeframe over which murine cardiomyocytes lose the ability to proliferate [3, 6]
The expression of agrin, laminin-α2, DG and Yes associated protein (YAP) were very similar between the 24 year old and 43 year old (Figure 1), and the results of the other patients were normalized to the average expression in these two adult patients
Summary
One major challenge in cardiovascular medicine is the loss of proliferative capacity of mammalian cardiomyocytes shortly after birth, rendering the adult heart unable to repair itself following an injury such as a myocardial infarction [1, 2]. The transcription factor YAP promotes growth in cardiac tissue [12], and the work of Bassat and coworkers [3] suggests that, in neonatal cardiomyocytes, agrin plays a vital role in promoting cardiomyocyte proliferation through binding to the ECM protein dystroglycan (DG). DG is part of a larger transmembrane complex, the dystrophin-glycoprotein complex, and is composed by two subunits, the highly glycosylated extracellular α-DG and the transmembrane β-DG, that interact non-covalently to form a bridge between the ECM and the actin cytoskeleton [13, 14] It was hypothesized [3] that binding of agrin to α-DG in the myocardium causes a conformational change in the dystrophin-glycoprotein complex, which in turn prevents β-DG from binding YAP intracellularly, allowing its localization to the nucleus, where YAP can exert its co-transcriptional activity and promote proliferation [reviewed in [15]]. Agrin based therapies have proven successful at inducing repair in animal models of cardiac injury, whether similar pathways exist in the human heart is unknown
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