Etanercept Ameliorates Cardiac Fibrosis in Rats with Diet-Induced Obesity

Abstract

Diet-induced obesity (DIO) is considered the main risk factor for cardiovascular diseases. Increases in the plasma levels of tumor necrosis factor alpha (TNF-α) is associated with DIO. Etanercept, a TNF-α inhibitor, has been shown to alleviate cardiac hypertrophy. To investigate the effect of etanercept on cardiac fibrosis in DIO model, rats on high fat diet (HFD) were subdivided into two groups: the etanercept group and vehicle group. Cardiac injury was identified by classic methods, while fibrosis was characterized by histological analysis of the hearts. Etanercept treatment at 0.8 mg/kg/week twice weekly by subcutaneous injection effectively alleviates the cardiac fibrosis in HFD-fed rats. STAT3 activation seems to be induced in parallel with fibrosis-related gene expression in the hearts of HFD-fed rats. Decreased STAT3 activation plays a role in the etanercept-treated animals. Moreover, fibrosis-related genes are activated by palmitate in parallel with STAT3 activation in H9c2 cells. Etanercept may inhibit the effects of palmitate, but it is less effective than a direct inhibitor of STAT3. Direct inhibition of STAT3 activation by etanercept seems unlikely. Etanercept has the ability to ameliorate cardiac fibrosis through reduction of STAT3 activation after the inhibition of TNF-α and/or its receptor.

Cytokine modulation by etanercept ameliorates metabolic syndrome and its related complications induced in rats administered a high-fat high-fructose diet

“…These findings were consistent with the reports of Hsu et al, who observed that ETA administration significantly reduced HFD-induced obesity 14 . The ability of ETA to inhibit any increase in body weight is attributed to its inhibition of TNF-α, the key inducer of adipogenesis and obesity 42 , 44 .…”

“…Previous studies have reported that TNF-α influences the adipose production of profibrogenic factors, such as leptin, and inhibits the expression and activity of adiponectin 47 , 48 . This resulted in significantly elevated adiponectin levels and normalized leptin levels in the ETA-treated group, which competitively prevented the binding of TNF-α to its receptor, causing its inhibition 14 . Consequently, ETA ameliorated adipocyte dysfunction and aids in the prevention of intrahepatic lipid accumulation and the enhancement of both insulin sensitivity 49 and endothelial functions that counteract hypertension, as detected in the present study 27 .…”

“…For effective induction of MS, rats in the group 2 (the HFHF group) and group 3 (the ETA-treated group) were administered high-fat diet (HFD) that was constructed according to Lasker, S. et al who prepared it from normal rat feed, beef tallow, sucrose, and condensed milk, which represent ~ 14% proteins, 37% carbohydrates, and 49% fat from the perspective of the caloric content 9 , along with fructose solution dissolved in purified water (60%) intragastrically once daily 4 . From week 4 to the end of the 8-week experimental period, rats in group 3 received ETA (0.8 mg/kg twice weekly, subcutaneously) 14 .…”

“…To date, ETA is mainly used to treat TNF-α-related disorders, such as rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, and psoriasis 12 . Previous studies have indicated that TNF-α is the key inducer of the well-defined features of MS, such as obesity, impaired glucose utilization, IR, dyslipidemia, and hepatotoxicity 13 , 14 . Although ETA was withdrawn from the clinical trial which was investigating its therapeutic effects in the treatment of heart failure as during the trial period ETA did not show therapeutic effectiveness 15 , it is worth noting that, clinical trials are still undergoing investigation of the efficacy and safety of ETA in treating different metabolic disorders in which ETA showed promising results not only in clinical trials that targeted metabolic disorders accompanied by autoimmune diseases 16 – 19 but also, in clinical trials targeting patients suffering from metabolic diseases only 20 – 22 .…”

“…Besides, several articles concluded that ETA will be one of the future treatments that still need further studies either in type 2 diabetes 23 or even in chronic heart failure 24 , 25 . All that opened the door for further experimental studies to be held for additional investigations of ETA in the treatment of different metabolic diseases 14 , 26 – 28 . Regarding its safety, all the previously mentioned clinical and experimental studies confirmed that after close monitoring of the patients who participated in the trial, ETA was safe, effective, and tolerable within the used dose and trial period that was indicated in each study.…”