Abstract

Objective

The present study aimed to evaluate the protective role of cilengitide (CGT), an integrin αvβ3 and αvβ5 inhibitor, on doxorubicin (DOX)-induced myocardial fibrosis and cardiac dysfunction in a rat model. Methods. Forty male rats were randomly divided into four groups: DOX (n = 12), intraperitoneal (i.p.) injection of DOX 0.8 ∼ 1.0 mg/kg three times a week for up to 6 weeks, then saline i.p. three times a week for another 3 weeks; CGT (n = 8), CGT 10 mg/kg, i.p. three times a week for 9 weeks; DOX + CGT (n = 12), DOX and CGT co-administration as above for 6 weeks, then CGT alone for another 3 weeks; Control (n = 8), saline i.p. three times a week for 9 weeks. Echocardiography, serum procollagen I C-terminal propeptide (PICP) procollagen III N-terminal propeptide (PIIINP) and C telopeptide type I (CTX-I) were evaluated at baseline and 3, 6 and 9 weeks after initial DOX administration for all surviving rats. The heart tissues were then harvested for myocardial hydroxyproline (HYP) evaluation, qRT-PCR, and western blotting. Results. CGT attenuated DOX-induced eccentric remodeling by improving relative wall thickness at the 9th week. CGT also improved systolic function at the 9th week and diastolic function at the 6th and 9th week. CGT reduced myocardial HYP and serum PICP, PIIINP, CTX-I, and the PICP/PIIINP ratio. RT-PCR and western blot showed that CGT blocked the TGF-β1/SMAD3 pathway and mitigating extracellular matrix turnover. Conclusions. CGT exerted a cardioprotective effect against doxorubicin-induced fibrosis and improved cardiac function.

中文翻译：

---

双整合素 αvβ3 和 αvβ5 阻断通过减少多柔比星诱导的心肌病大鼠模型的纤维化来减轻心功能障碍

摘要

客观的

本研究旨在评估西仑吉肽（CGT）（一种整合素αvβ3和αvβ5抑制剂）对阿霉素（DOX）诱导的大鼠模型心肌纤维化和心功能不全的保护作用。方法。将 40 只雄性大鼠随机分为 4 组：DOX（n  = 12），腹腔（ip）注射 DOX 0.8 ∼ 1.0 mg/kg，每周 3 次，持续长达 6 周，然后腹腔注射生理盐水，每周 3 次，持续 3 周。几周；CGT ( n  = 8)，CGT 10 mg/kg，腹膜内注射，每周 3 次，持续 9 周；DOX + CGT ( n  = 12)，DOX 和 CGT 如上所述共同给药 6 周，然后单独 CGT 再给药 3 周；对照（n  = 8），每周 3 次腹腔注射生理盐水，持续 9 周。对所有存活大鼠在基线以及初次给予 DOX 后 3、6 和 9 周进行超声心动图、血清 I 型前胶原 C 端前肽 (PICP)、III 型前胶原 N 端前肽 (PIIINP) 和 I 型 C 端肽 (CTX-I) 评估。然后收获心脏组织用于心肌羟脯氨酸（HYP）评估、qRT-PCR 和蛋白质印迹。结果。CGT 通过在第 9 周改善相对壁厚来减弱 DOX 引起的偏心重塑。CGT 还改善了第 9 周的收缩功能和第 6 周和第 9 周的舒张功能。CGT 降低心肌 HYP 和血清 PICP、PIIINP、CTX-I 以及 PICP/PIIINP 比值。RT-PCR 和蛋白质印迹显示 CGT 阻断 TGF-β1/SMAD3 通路并减轻细胞外基质周转。结论。CGT 对阿霉素诱导的纤维化发挥心脏保护作用，并改善心脏功能。