BACKGROUND Apelin is an endogenous prepropeptide that regulates cardiac homeostasis and various physiological processes. Intravenous injection has been shown to improve cardiac contractility in patients with heart failure. However, its short half-life prevents studying its impact on left ventricular remodeling in the long term. Here, we aim to study whether microparticle-mediated slow release of apelin improves heart function and left ventricular remodeling in mice with myocardial infarction (MI). METHODS A cardiac patch was fabricated by embedding apelin-containing microparticles in a fibrin gel scaffold. MI was induced via permanent ligation of the left anterior descending coronary artery in adult C57BL/6J mice followed by epicardial patch placement immediately after (acute MI) or 28 days (chronic MI) post-MI. Four groups were included in this study, namely sham, MI, MI plus empty microparticle-embedded patch treatment, and MI plus apelin-containing microparticle-embedded patch treatment. Cardiac function was assessed by transthoracic echocardiography. Cardiomyocyte morphology, apoptosis, and cardiac fibrosis were evaluated by histology. Cardioprotective pathways were determined by RNA sequencing, quantitative polymerase chain reaction, and Western blot. RESULTS The level of endogenous apelin was largely reduced in the first 7 days after MI induction and it was normalized by day 28. Apelin-13 encapsulated in poly(lactic-co-glycolic acid) microparticles displayed a sustained release pattern for up to 28 days. Treatment with apelin-containing microparticle-embedded patch inhibited cardiac hypertrophy and reduced scar size in both acute and chronic MI models, which is associated with improved cardiac function. Data from cellular and molecular analyses showed that apelin inhibits the activation and proliferation of cardiac fibroblasts by preventing transforming growth factor-β-mediated activation of Smad2/3 (supporessor of mothers against decapentaplegic 2/3) and downstream profibrotic gene expression. CONCLUSIONS Poly(lactic-co-glycolic acid) microparticles prolonged the apelin release time in the mouse hearts. Epicardial delivery of the apelin-containing microparticle-embedded patch protects mice from both acute and chronic MI-induced cardiac dysfunction, inhibits cardiac fibrosis, and improves left ventricular remodeling.

中文翻译：

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微粒介导的 Apelin 递送可改善心肌梗塞后小鼠的心脏功能。


背景Apelin是调节心脏稳态和各种生理过程的内源性前原肽。静脉注射已被证明可以改善心力衰竭患者的心肌收缩力。然而，其半衰期短，无法研究其对左心室重构的长期影响。在这里，我们的目的是研究微粒介导的 apelin 缓慢释放是否可以改善心肌梗塞 (MI) 小鼠的心功能和左心室重塑。方法 通过将含有 apelin 的微粒嵌入纤维蛋白凝胶支架中来制造心脏补片。通过永久性结扎成年 C57BL/6J 小鼠的左前降支冠状动脉，然后在 MI 后（急性 MI）或 28 天（慢性 MI）后立即放置心外膜补片来诱导 MI。本研究包括四组，即假手术组、MI组、MI加空微粒嵌入贴片治疗组、MI加上含有apelin的微粒嵌入贴片治疗组。通过经胸超声心动图评估心脏功能。通过组织学评估心肌细胞形态、细胞凋亡和心脏纤维化。通过 RNA 测序、定量聚合酶链式反应和蛋白质印迹确定心脏保护途径。结果 MI 诱导后的前 7 天内，内源性 apelin 水平大幅降低，并在第 28 天时恢复正常。封装在聚乳酸-乙醇酸共聚物微粒中的 Apelin-13 显示出长达 28 天的持续释放模式。在急性和慢性 MI 模型中，使用含有 apelin 的微粒嵌入贴片进行治疗可抑制心脏肥大并减少疤痕大小，这与改善心脏功能有关。 细胞和分子分析数据表明，apelin 通过阻止转化生长因子-β 介导的 Smad2/3（母亲对十肢瘫痪 2/3 的支持者）的激活和下游促纤维化基因的表达来抑制心脏成纤维细胞的激活和增殖。结论 聚乳酸-乙醇酸共聚物微粒延长了小鼠心脏中 apelin 的释放时间。心外膜递送含有 apelin 的微粒嵌入贴片可保护小鼠免受急性和慢性 MI 引起的心脏功能障碍，抑制心脏纤维化，并改善左心室重塑。