Department of Internal Medicine and Cardiovascular Sciences, University Federico II, Via Sergio Pansini 5, Naples, Italy.
Eur J Heart Fail. 2011 Dec;13(12):1264-74. doi: 10.1093/eurjhf/hfr143. Epub 2011 Nov 1.
Strategies to prevent adverse left ventricular (LV) remodelling after myocardial infarction have included several traditional approaches and novel cell-based or gene therapies. Delivery of growth factors in post-infarction heart failure has emerged as a valuable alternative strategy. Our aim was to investigate the effects of sequential release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) from biodegradable gelatin microspheres in experimental heart failure.
Gelatin hydrogel microspheres were known to guarantee a sustained release of encapsulated growth factors, characterized by an initial burst followed by a slower release. Rats with moderate myocardial infarction were randomized to receive empty microspheres (MI), microspheres loaded with IGF-1 or VEGF, or a combination thereof (DUAL). Myocardial injections of microspheres were performed at the time of surgery, and treatment lasted 4 weeks. Echocardiography, LV catheterization, morphometric histology and immunohistochemistry, and molecular assessment of downstream mediators [e.g. Akt, endothelial nitric oxide synthase (eNOS), and sarco/endoplasmic reticulum calcium ATPase-2 (SERCA-2)] were assessed at the end of the treatment period. Infarct sizes were 33 ± 2, 28 ± 4, 24 ± 3, and 16 ± 3% in the MI, IGF-1, VEGF, and DUAL groups, respectively. IGF-1 attenuated LV remodelling, improved LV systolic and diastolic function, increased myocyte size, and reduced apoptotic deaths, capillary loss, and indexes of inflammation. VEGF-treated animals displayed a marked myocardial neoangiogenesis that led to the formation of mature vessels if combined with IGF-1 delivery. Downstream effects of IGF-1 were principally mediated by the Akt-mTOR (mammalian target of rapamycin)-dependent pathway, and both growth factors, particularly VEGF, induced a robust and sustained increase of eNOS.
IGF-1 and VEGF exerted complementary therapeutic effects in post-infarction heart failure. Biodegradable gelatin microspheres provide sustained and controlled growth factor release locally, exposing myocardial tissue without the side effects of systemic administration.
预防心肌梗死后左心室（LV）重构的策略包括多种传统方法和新型基于细胞或基因的治疗方法。在心肌梗死后心力衰竭中，生长因子的传递已成为一种有价值的替代策略。我们的目的是研究从可生物降解的明胶微球中顺序释放血管内皮生长因子（VEGF）和胰岛素样生长因子-1（IGF-1）对实验性心力衰竭的影响。
明胶水凝胶微球能够保证包封生长因子的持续释放，其特征是初始突释后缓慢释放。中度心肌梗死大鼠随机分为接受空微球（MI）、负载 IGF-1 或 VEGF 的微球或两者组合（DUAL）的组。微球在手术时心肌内注射，治疗持续 4 周。在治疗期末进行超声心动图、左心室导管插入术、形态计量学组织学和免疫组织化学以及下游介质的分子评估[例如 Akt、内皮型一氧化氮合酶（eNOS）和肌浆/内质网钙 ATP 酶-2（SERCA-2）]。MI、IGF-1、VEGF 和 DUAL 组的梗死面积分别为 33 ± 2%、28 ± 4%、24 ± 3%和 16 ± 3%。IGF-1 减轻 LV 重构，改善 LV 收缩和舒张功能，增加心肌细胞大小，减少细胞凋亡、毛细血管丢失和炎症指标。VEGF 处理的动物表现出明显的心肌新生血管形成，如果与 IGF-1 联合给药，可形成成熟的血管。IGF-1 的下游作用主要通过 Akt-mTOR（哺乳动物雷帕霉素靶蛋白）依赖性途径介导，两种生长因子，特别是 VEGF，诱导了强大而持续的 eNOS 增加。
IGF-1 和 VEGF 在心肌梗死后心力衰竭中发挥互补的治疗作用。可生物降解的明胶微球在局部提供持续和控制的生长因子释放，暴露心肌组织而没有全身给药的副作用。
