PDF(Pubmed)
Abstract：
Fibroblast growth factor (FGF)21 is a peptide hormone that improves mitochondrial function and energy metabolism, and the deficiency of its co‑receptor β‑klotho (KLB) causes decreased FGF21 sensitivity. The present study examined whether the cardiac delivery of plasmids containing the KLB gene via ultrasound‑targeted microbubble destruction (UTMD) enhances the efficacy of FGF21 against heart failure post‑acute myocardial infarction (AMI). For this purpose, the levels of FGF21 in patients and rats with heart dysfunction post‑infarction were determined using ELISA. Sprague‑Dawley rats received the 3X UTMD‑mediated delivery of KLB@cationic microbubbles (KLB@CMBs) 1 week following the induction of AMI. Echocardiography, histopathology and biochemical analysis were performed at 4 weeks following the induction of AMI. The results revealed that patients with heart failure post‑infarction had higher serum FGF21 levels than the healthy controls. However, the downstream signal, KLB, but not α‑klotho, was reduced in the heart tissues of rats with AMI. As was expected, treatment with FGF21 did not substantially attenuate heart remodeling post‑infarction. It was found that decreased receptors KLB in the heart may result in the insensitivity to FGF21 treatment. In vivo, the UTMD technology‑mediated delivery of KLB@CMBs to the heart significantly enhanced the effects of FGF21 administration on cardiac remodeling and mitochondrial dysfunction in the rats following infarction. The delivery of KLB to the heart by UTMD and the administration of FGF21 attenuated mitochondrial impairment and oxidative stress by activating nuclear factor erythroid 2‑related factor 2 signals. On the whole, the present study demonstrates that the cardiac delivery of KLB significantly optimizes the cardioprotective effects of FGF21 therapy on adverse heart remodeling. UTMD appears a promising interdisciplinary approach with which to improve heart failure post‑myocardial infarction.
摘要：
成纤维细胞生长因子（FGF）21是一种肽激素，可改善线粒体功能和能量代谢，其共同受体β-klotho（KLB）的缺乏导致FGF21敏感性降低。本研究检查了通过超声靶向微泡破坏（UTMD）心脏递送含有KLB基因的质粒是否会增强FGF21对急性心肌梗死（AMI）后心力衰竭的疗效。为此,使用ELISA测定梗死后心功能不全患者和大鼠的FGF21水平。诱导AMI后1周，Sprague-Dawley大鼠接受了3XUTMD介导的KLB@阳离子微泡（KLB@CMBs）递送。超声心动图,在AMI诱导后4周进行组织病理学和生化分析.结果显示，梗死后心力衰竭患者的血清FGF21水平高于健康对照组。然而,下游信号，KLB,但不是α-klotho,在AMI大鼠的心脏组织中减少。正如预期的那样，FGF21治疗并未显著减轻梗死后心脏重塑.发现心脏中受体KLB降低可能导致对FGF21治疗不敏感。在体内,UTMD技术介导的KLB@CMBs向心脏的递送显著增强了FGF21给药对梗死后大鼠心脏重塑和线粒体功能障碍的影响.通过UTMD将KLB递送至心脏和FGF21的施用通过激活核因子红系2相关因子2信号来减轻线粒体损伤和氧化应激。总的来说,本研究表明,KLB的心脏递送显著优化了FGF21治疗对不良心脏重塑的心脏保护作用.UTMD似乎是一种有希望的跨学科方法，可以改善心肌梗死后的心力衰竭。
