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ASSA14-03-43 Novel therapeutic uses of triptolide in reversing isoprenaline-induced cardiac remodelling in Wistar rats

Background Nowadays, chronic heart failure (CHF) is a global health problem in the elderly. Over 650 thousand new cases are diagnosed every year in the United States. Previous studies indicate that immune-inflammatory activation plays an important role in the pathogenesis of cardiac remodelling in CHF patients. PG-490, triptolide (TPL), is a diterpene triepoxide with potent immunosuppressive and anti-inflammatory properties and has been used in China for centuries to treat immune-related disorders. However, the effects of TPL on CHF and cardiac remodelling remain unclear. Objective To determine whether TPL can protect myocardial fibrosis and improve cardiac function in isoprenaline-induced CHF rats. Methods Age matched male Wistar rats were used in this study. CHF and cardiac remodelling model was established by hypodermic injection of isoprenaline for ten days. The rats were randomly divided to receive placebo, TPL (20 or 100 μg/kg/d, i.g.) or captopril for six weeks. Cardiac remodelling markers including ventricular mass, collagen volume fraction, perivascular collagen area, collagenI and hydroxyproline concentration were studied. Echocardiography, Masson staining, immunohistochemistry, western blot and real-time PCR were performed. The protein and mRNA expression of PTEN (phosphatase and tensin homolog deleted on chromosome ten) were analysed. Results Compared to the untreated CHF rats, the cardiac remodelling markers, LVEDD (8.40 ± 0.52 mm vs 6.11 ± 0.58 mm) and LVESD (6.44 ± 0.93 mm vs 4.49 ± 0.38 mm) were significantly lower in TPL-treated (100 μg/kg/d) rats (p < 0.05, n = 8). TPL treatment also improved LVEF levels (46.44 ± 3.50% vs 60.89 ± 3.10%, p < 0.05). Besides, the expressions of PTEN protein (0.11 ± 0.05 vs 0.51 ± 0.28, Figure 1) and mRNA (0.22 ± 0.06 vs 0.52 ± 0.01) were higher in TPL-treated rats (p < 0.05, n = 3). No damage of renal or liver function was detected in these rats. Furthermore, we also found that TPL can accelerate myocardial fibroblast cell apoptosis and upregulate PTEN signalling in vitro . Abstract ASSA14-03-43 Figure 1 Effects of TPL on the expression of PTEN protein. TPL = triptolide; PTEN = phosphatase and tensin homolog deleted on chromosome ten; A: normal rats; B: cardiac remodeling rats; C: TPL 20 μg/kg/d; D: TPL 100 μg/kg/d; E: captopril 15 mg/kg/d Conclusions Our findings indicate that TPL could alleviate myocardial remodelling and improve cardiac function in rats by upregulating PTEN signalling pathway. TPL may be a potential therapeutic drug for CHF.