Department of Cardiovascular Diseases, Physiology and Biomedical Engineering, Center for Regenerative Medicine, Mayo Clinic Arizona, Scottsdale (L.T., H.Q., B.X., V.N., P.L., H.A., A. Yang, A. Yu, M.J., W.Z.).
Department of Surgery-Transplant and Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha (Y.S., J.X.).
Circ Res. 2024 Sep 13;135(7):777-798. doi: 10.1161/CIRCRESAHA.124.324608. Epub 2024 Aug 15.
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).
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.
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.
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.
Apelin 是一种内源性前肽，可调节心脏稳态和各种生理过程。静脉注射已被证明可改善心力衰竭患者的心脏收缩力。然而，其半衰期短使得难以长期研究其对左心室重构的影响。在这里，我们旨在研究载有 Apelin 的微粒介导的缓慢释放是否能改善心肌梗死（MI）小鼠的心脏功能和左心室重构。
通过将载有 Apelin 的微粒嵌入纤维蛋白凝胶支架中制备心脏贴片。通过结扎成年 C57BL/6J 小鼠的左前降支冠状动脉诱导 MI，随后在 MI 后即刻（急性 MI）或 28 天（慢性 MI）进行心外膜贴片放置。本研究包括 4 组，即假手术组、MI 组、MI 加空微粒嵌入贴片治疗组和 MI 加载有 Apelin 的微粒嵌入贴片治疗组。通过经胸超声心动图评估心功能。通过组织学评估心肌细胞形态、凋亡和心脏纤维化。通过 RNA 测序、定量聚合酶链反应和 Western blot 确定心脏保护途径。
MI 诱导后前 7 天内内源性 Apelin 水平大幅降低，第 28 天恢复正常。包封在聚（乳酸-共-乙醇酸）微粒中的 Apelin-13 显示出长达 28 天的持续释放模式。载有 Apelin 的微粒嵌入贴片治疗可抑制急性和慢性 MI 模型中的心脏肥大并减少疤痕大小，从而改善心脏功能。细胞和分子分析数据表明，Apelin 通过防止转化生长因子-β介导的 Smad2/3（抑制母亲对抗 decapentaplegic 2/3）激活和下游促纤维化基因表达来抑制心肌成纤维细胞的激活和增殖。
聚（乳酸-共-乙醇酸）微粒延长了 Apelin 在小鼠心脏中的释放时间。载有 Apelin 的微粒嵌入贴片的心外膜递送可保护小鼠免受急性和慢性 MI 引起的心脏功能障碍、抑制心脏纤维化和改善左心室重构。
