Original articleDeath receptor 5 contributes to cardiomyocyte hypertrophy through epidermal growth factor receptor transactivation
Introduction
Cardiovascular disease is a leading cause of morbidity and mortality worldwide [1]. A common characteristic and main contributor to most cardiac diseases is cell death, which occurs through two main mechanisms, necrosis and apoptosis [2]. There are two main pathways through which apoptosis occurs, the intrinsic pathway that uses mitochondrial pathways and has been extensively studied in the heart, and extrinsic pathway that occurs through cell surface death receptors [3]. Some extrinsic pathways, such as tumor necrosis factor (TNF)-α, are also well characterized in the heart however, there are numerous other death receptors that have been virtually unstudied in the context of cardiovascular disease and heart failure [4].
Whole transcriptome analysis in a chronic catecholamine administration model of heart failure identified TNF-related apoptosis inducing ligand (TRAIL; also known as Tnfsf10 and CD253) and its receptor DR5 (TRAIL-R2) as being altered with cardioprotective β-adrenergic receptor signaling in mouse hearts [5]. There have been virtually no studies investigating the role of TRAIL/DR5 in the heart. However, TRAIL and its three receptors, DR4, DR5 and DcR1, are moderately to highly expressed at the transcript and protein level in the human and chimpanzee heart [6,7]. Rodents express a single death domain containing receptor for TRAIL, DR5, which is homologous to human DR4 and DR5 and also have high DR5 expression at the mRNA level in the heart [8]. Furthermore, in the last several years, multiple clinical studies have identified TRAIL or DR5 as biomarkers in the prediction of severity and mortality following myocardial infarction and in heart failure development risk [[9], [10], [11]]. In a study employing proteomics on serum of patients following acute myocardial infarction, DR5 levels were found to be one of the most powerful biomarkers in predicting long-term mortality with low levels of circulating DR5 being associated with worsened outcome [9]. Additionally, in a longitudinal study spanning over a decade, DR5 was identified as a biomarker for predicting the development of heart failure in elderly patients and associated with worsened left ventricular function with high levels of circulating DR5 being associated with worsened systolic function [10].
The majority of TRAIL research has focused on therapeutically targeting the TRAIL system for the treatment of cancer due to its ability to selectively induce apoptosis in cancer cells [12]. Many non-transformed cell types are resistant to TRAIL-induced apoptosis, suggesting non-canonical TRAIL/DR5 functions in non-cancerous cell types [13]. Pre-clinical and phase I clinical trials assessing the safety of TRAIL administration have demonstrated no toxicity however, the cardiac effects were not carefully examined and treatment durations were short [12,[14], [15], [16]]. While the literature is sparse, there is evidence to suggest that TRAIL signaling in relevant cell types to the heart do not lead to apoptosis. Dermal fibroblasts and umbilical artery smooth muscle cells are resistant to TRAIL induced apoptosis in spite of expressing both DR4 and DR5 [17]. In skeletal myoblasts, TRAIL has a non-canonical function of promoting differentiation [18]. In a separate study, a number of human fibroblast cell lines were found express DR4 and DR5 but to be resistant to TRAIL-induced apoptosis due to differences in the ability to activate caspase 8 compared with cancer cell lines [19]. It is not clear what causes resistance to TRAIL in non-transformed cell types, it is likely that alterations in the apoptotic machinery attribute to these differences [17]. These findings demonstrate the necessity of understanding the function of TRAIL outside of tumor cells since TRAIL is secreted by most cells types [20], including cardiomyocytes [5], and it is becoming increasingly apparent that the role of TRAIL differs in non-transformed cell types. Furthermore, while minimal research has been performed in cell types closely relevant to the heart, there have been no investigation into the function of the TRAIL/DR5 system in the heart, in spite of its high expression and strong correlation with cardiovascular disease in humans [[9], [10], [11]]. The purpose of this study was to investigate the role of DR5 activation in the heart with the hypothesis that DR5 does not induce cardiomyocyte apoptosis but initiates non-canonical signaling to promote cardiomyocyte growth and survival. Using DR5 agonist administration in vitro and in vivo, cardiomyocyte death was not observed, but increased hypertrophy occurred through the activation of ERK1/2. EGFR transactivation occurred with DR5 activation and specific inhibitors of matrix metalloprotease (MMP) and EGFR prevented ERK1/2 activation and hypertrophy. Hypertrophy occurred through the ERK1/2-mediated activation of the transcription factor GATA4 to promote pro-hypertrophic gene transcription. Taken together, these findings identify novel role for DR5 in cardiomyocytes where activation does not promote cell death, but results in hypertrophy through ERK1/2-EGFR-GATA4 dependent mechanisms.
Section snippets
Animals
C57BL/6 mice (male; 8–12 weeks old) were randomly assigned to treatment group and administered MD5–1 antibody (BioXCell, catalog # BE0161; 2 mg/kg) or IgG control (BioXCell, catalog # BE0091; 2 mg/kg) via intraperitoneal injection every 3 days. Another group was administered vehicle (10% DMSO in sterile saline) or bioymifi (5 mg/kg/d) via osmotic minipump (Alzet). Mice were euthanized after 2 weeks administration, hearts were excised and flash frozen in liquid nitrogen for use in biochemical
DR5 activation does not induce cardiomyocyte death
Few studies have examined DR5 expression in the heart however, it is thought to be moderately to highly expressed at the transcript and protein level in the human and chimpanzee heart [6,7] and highly expressed at the mRNA level in the murine heart [8]. To confirm DR5 protein expression in mouse and rat, hearts from C57BL6 mice were subjected to enzymatic digestion to isolate cardiomyocyte and non-cardiomyocyte cells of the heart and DR5 expression was examined by immunoblot. DR5 expression was
Discussion
Cardiomyocyte growth, survival and death are critical contributors to the outcome of heart failure. The TRAIL/DR5 system has been implicated in multiple types of heart failure [[9], [10], [11]], but their role in the heart has never been established. Initial characterization of DR5 expression in mice identified high expression in heart, lung and kidney and moderate to high expression in the human and chimpanzee heart [6,7], however, very little is known about the role of TRAIL and DR5 in the
Funding
This work was supported by American Heart Association Scientific Development Grant 17SDG33400114 (L.A.G.).
Declaration of Competing Interest
The authors have declared that no conflict of interest exists.
References (67)
- et al.
beta-Adrenergic receptor-mediated transactivation of epidermal growth factor receptor decreases cardiomyocyte apopotsis through differential subcellular activation of ERK1/2 and Akt
J. Mol. Cell. Cardiol.
(2014) - et al.
Cell surface death receptor signaling in normal and cancer cells
Semin. Cancer Biol.
(2003) TRAIL-induced signalling and apoptosis
Toxicol. Lett.
(2003)- et al.
Non-canonical role for the TRAIL receptor DR5/FADD/caspase pathway in the regulation of MyoD expression and skeletal myoblast differentiation
Differentiation
(2009) - et al.
The Deubiquitinase inhibitor PR-619 sensitizes normal human fibroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cell death
J. Biol. Chem.
(2016) - et al.
Identification and characterization of a new member of the TNF family that induces apoptosis
Immunity
(1995) - et al.
Life and death in the thymus—cell death signaling during T cell development
Curr. Opin. Cell Biol.
(2010) - et al.
TRAIL-activated EGFR by Cbl-b-regulated EGFR redistribution in lipid rafts atagonises TRAIL-induced apoptosis in gastric cancer cells
Eur. J. Cancer
(2012) - et al.
Simultaneous inhibition of epidermal growth factor receptor (EGFR) signaling and enhanced activation of tumor necrosis factor-related apoptosis-inducin ligand (TRAIL) receptor-mediated apoptosis induction by an scFv:sTRAIL fusion protein with specificity for human EGFR
J. Biol. Chem.
(2005) - et al.
Serum levels of tumor necrosis factor-related apoptosis-inducing ligand correlate with the severity of pulmonary hypertension
Pulm. Pharmacol. Ther.
(2015)
MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors
J. Biol. Chem.
The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo
J. Biol. Chem.
Epidermal growth factor receptor transactivation mediates tumor necrosis factor-induced hepatocyte replication
J. Biol. Chem.
The epidermal growth factor receptor mediates tumor necrosis facto-alpha-induced activation of the ERK/GEF-H1/RhoA pathway in tubular epitelium
J. Biol. Chem.
Cell signaling by receptor tyrosine kinases
Cell
Prognostic value of osteoprotegerin in chronic heart failure: the GISSI-HF trial
Am. Heart J.
Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction
J. Am. Coll. Cardiol.
Heart disease and stroke statistics-2017 update: a report from the American heart association
Circulation
Mechanisms of cell death in heart disease
Arterioscler. Thromb. Vasc. Biol.
The mitochondrial death pathway and cardiac myocyte apoptosis
Circ. Res.
Recent insights into the role of tumor necrosis factor in the failing heart
Heart Fail. Rev.
An antagonist decoy receptor and a death domain-containing receptor for TRAIL
Science
Tissue distribution of the death ligand TRAIL and its receptors
J. Histochem. Cytochem.
GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction
Eur. J. Prev. Cardiol.
Circulating proteins as predictors of incident of heart failure in the elderly
Eur. J. Heart Fail.
Roles and clinical applications of OPG and TRAIL as biomarkers in cardiovascular disease
Biomed. Res. Int.
Safety and antitumor activity of recombinant soluble Apo2 ligand
J. Clin. Invest.
Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo
Nat. Med.
Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer
J. Clin. Oncol.
Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and bevacizumad in patients with advanced non-squamous non-small-cell lung cancer
J. Clin. Oncol.
Resistance to TRAIL in non-transformed cells is sdue to multiple redundant pathways
Cell Death Dis.
Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling
Theranostics
Small-molecule activation of the TRAIL receptor DR5 in human cancer cells
Nat. Chem. Biol.
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