Abstract
We aimed to investigate the effect of etanercept, a tumor necrosis factor-α (TNF-α) inhibitor, on rat cardiomyocyte hypertrophy and its underlying mechanism. Primary neonatal rat cardiomyocytes were isolated from Sprague-Dawley rats. The model of rat cardiomyocyte hypertrophy was induced by endothelin, and then treated with different concentrations of etanercept (1, 10, and 50 μM). After treatment, cell counts, viability and cell apoptosis were evaluated. The mRNA levels of myocardial hypertrophy marker genes, including atrial natriuretic factor (ANF), matrix metalloproteinase (MMP)-9 and MMP-13, were detected by qRT-PCR, and the expressions of apoptosis-related proteins (Bcl-2 and Bax) were measured by western blotting. The protein levels of transforming growth factor-β1 (TGF-β1), interleukin (IL)-1β, IL-6, leukemia inhibitory factor (LIF) and cardiotrophin-1 (CT-1) were determined using enzyme linked immunosorbent assay (ELISA) kits. In the present study, TNF-α level in cardiomyocytes with hypertrophy was significantly enhanced (P<0.05). Compared to the model group, cell number and viability were significantly increased and ratio of apoptotic cells was reduced by etanercept (P<0.05, P<0.01, or P<0.001). In addition, etanercept remarkably reduced the mRNA levels of ANF, MMP-9 and MMP-13, inhibited the expression of Bax, and increased the expression of Bcl-2 compared to the model group (P<0.05). ELISA results further showed that etanercept lowered the levels of IL-1β, IL-6, LIF and CT-1 but not TGF-β1 compared to the model group (P<0.05). Etanercept may protect rat cardiomyocytes from hypertrophy by inhibiting inflammatory cytokines secretion and cell apoptosis.
Highlights
Cardiomyocyte hypertrophy is a common pathological change of progressive cardiac function failure, which can induce increased ventricular stress, declined cardiac function, cardiomyocyte death and tissues fibrosis [1]
The results showed that etanercept remarkably reduced the mRNA levels of these markers in comparison with endothelin-induced cardiomyocyte hypertrophy cell model (Po0.05, Figure 2A–C)
Cardiomyocytes treated with endothelin alone acted as the model, and non-treated cardiomyocytes acted as the control
Summary
Cardiomyocyte hypertrophy is a common pathological change of progressive cardiac function failure, which can induce increased ventricular stress, declined cardiac function, cardiomyocyte death and tissues fibrosis [1]. Previous studies have shown that adaptive cardiomyocyte hypertrophy is related to interleukin-6 (IL-6) cytokines, growth hormone/insulin-like growth factor-1, and biomechanical stretch signaling, as well as the activation of the signal transducer and activator of transcription 3, the phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3b cascade, and extracellular signal-regulated kinases [4,5,6,7]. Activations of these signaling pathways have been proven to increase cardiomyocyte size and induce concentric hypertrophy in adaptive cardiomyocyte hypertrophy [4,5,6,7]. Tumor necrosis factor-a (TNF-a), angiotensin II and catecholamines [5,8], as well as c-Jun N-terminal kinase and p38 are all involved in cardiomyocyte apoptosis and cardiac fibrosis [9]
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