Abstract
The fibrotic response is involved in nearly all forms of heart failure and dysregulated responses can lead to enhanced cardiac dysfunction. TNF-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor (DR) 5, are associated with multiple forms of heart failure, but their role in the heart is poorly defined. Our previous study identified DR5 expression on cardiac fibroblasts however, the impact of DR5 on fibroblast function remains unexplored. To investigate the role of DR5 in cardiac fibroblasts, a variety of fibroblast functions were examined following treatment with the endogenous ligand, TRAIL, or small molecule agonist, bioymifi. DR5 activation did not induce apoptosis in naïve fibroblasts but activated ERK1/2 signaling to increase proliferation. However, upon activation and differentiation to myofibroblasts, DR5 expression was elevated, and DR5 agonists induced caspase 3 activation resulting in myofibroblast apoptosis. To investigate the impact of DR5 regulation of fibroblasts in vivo, a chronic isoproterenol administration model of heart failure was used. Wild-type (WT) mice receiving isoproterenol had increased hypertrophy, cardiomyocyte death, and fibrosis and decreased contractility compared to vehicle treated animals. DR5 knockout (KO) mice had no overt baseline phenotype however, following isoproterenol infusion, increased cardiomyocyte death and hypertrophy in comparison to isoproterenol treated WT animals was observed. DR5KO mice had an augmented fibrotic response with isoproterenol treatment compared with WT, which corresponded with additional decreases in contractility. These findings identify a dual role for DR5 in cardiac fibroblast function through enhanced naïve fibroblast proliferation, which switches to a pro-apoptotic function upon differentiation to myofibroblasts. This is important in heart failure where DR5 activation suppresses maladaptive remodeling and may represent a novel therapeutic target for the treatment of heart failure.
Highlights
Cardiac fibroblasts play an important role in the normal and pathological heart through their ability to respond to stress or injury and facilitate wound healing responses [1]
Our previous studies identified expression of DR5 on cardiac fibroblasts; at lower levels than cardiomyocytes [24]. This was confirmed in neonatal rat ventricular myocytes (NRVMs) and Neonatal rat ventricular fibroblast (NRVF) (Supplementary Figure 2), which identified roughly 50% of the expression of DR5 in NRVFs compared with NRVMs
To determine if DR5 activation results in cardiac fibroblast apoptosis, NRVFs were treated over time with the endogenous DR5 agonist, TNF-related apoptosis-inducing ligand (TRAIL), or the small molecule DR5 agonist, bioymifi, and apoptosis was examined using a caspase 3/7 activity assay
Summary
Cardiac fibroblasts play an important role in the normal and pathological heart through their ability to respond to stress or injury and facilitate wound healing responses [1]. This response contributes to most forms of heart disease, including those arising from ischemic and nonischemic etiologies, and represents an important protective and reparative process. Persistent myofibroblast activity has detrimental effects by augmenting cardiomyocyte death, increasing hypertrophy, and contributing to excessive extracellular matrix deposition. This decreases cardiac compliance and further progresses the disease. While targeting fibrosis has been an attractive therapeutic strategy for cardiac diseases, to date, clinical trials targeting fibrosis for the treatment of heart failure have been largely disappointing [6]
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