Resistin is a circulating mediator of insulin resistance mainly expressed in human monocytes and responsive to inflammatory stimuli. Recent clinical studies have connected elevated resistin levels with the development and severity of heart failure. To further our understanding of the role of human resistin in heart failure, we studied a humanized mouse model lacking murine resistin but transgenic for the human Retn gene (Hum-Retn mice), which exhibits basal and inflammation-stimulated resistin levels similar to humans. Specifically, we explored whether resistin underlies acute anthracycline-induced cardiotoxicity. Remarkably, doxorubicin (25mg/kg ip) led to a 4-fold induction of serum resistin levels in Hum-Retn mice. Moreover, doxorubicin-induced cardiotoxicity was greater in the Hum-Retn mice than in littermate controls not expressing human resistin (Retn(-/-)). Hum-Retn mice showed increased cardiac mRNA levels of inflammatory and cell adhesion genes compared with Retn(-/-) mice. Macrophages, but not cardiomyocytes, from Hum-Retn mice treated with doxorubicin in vitro showed dramatic induction of hRetn (human resistin) mRNA and protein expression. We also examined resistin levels in anthracycline-treated breast cancer patients with and without cardiotoxicity. Intriguingly, serum resistin levels in women undergoing anthracycline-containing chemotherapy increased significantly at 3 months and remained elevated at 6 months in those with subsequent cardiotoxicity. Further, elevation in resistin correlated with decline in ejection fraction in these women. These results suggest that elevated resistin is a biomarker of anthracycline-induced cardiotoxicity and may contribute in the development of heart failure via its direct effects on macrophages. These results further implicate resistin as a link between inflammation, metabolism, and heart disease.

译文

:抵抗素是胰岛素抵抗的循环介质,主要在人类单核细胞中表达,对炎症刺激有反应。最近的临床研究已将抵抗素水平升高与心力衰竭的发展和严重程度联系起来。为了进一步了解人类抵抗素在心力衰竭中的作用,我们研究了一种缺少鼠抵抗素但转为人类Retn基因(Hum-Retn小鼠)的人源化小鼠模型(Hum-Retn小鼠),其表现出与人类相似的基础和炎症刺激抵抗素水平。具体来说,我们探讨了抵抗素是否是急性蒽环类药物引起的心脏毒性的基础。值得注意的是,阿霉素(25mg / kg ip ip)导致Hum-Retn小鼠血清抵抗素水平提高了4倍。此外,在Hum-Retn小鼠中,阿霉素诱导的心脏毒性要比未表达人抵抗素(Retn(-/-))的同窝仔对照更大。与Retn(-/-)小鼠相比,Hum-Retn小鼠显示出炎症和细胞粘附基因的心脏mRNA水平升高。体外用阿霉素处理的Hum-Retn小鼠的巨噬细胞而非心肌细胞显示出hRetn(人抵抗素)mRNA和蛋白表达的显着诱导。我们还检查了蒽环类药物治疗的有或没有心脏毒性的乳腺癌患者的抵抗素水平。有趣的是,接受含蒽环类药物化疗的妇女的血清抵抗素水平在3个月时显着增加,而在随后发生心脏毒性反应的妇女中,在6个月时仍然升高。此外,这些女性的抵抗素升高与射血分数下降相关。这些结果表明,升高的抵抗素是蒽环类药物诱导的心脏毒性的生物标志物,并可能通过其对巨噬细胞的直接作用而导致心力衰竭的发展。这些结果进一步暗示抵抗素是炎症,代谢和心脏病之间的联系。

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