Maladaptive Remodeling in Aging Myocardium

左心室(LV)重构是细胞和细胞外基质(ECM)事件的总和， 它总是发生在心肌梗死(MI)之后，是临床上重要的预测指标 结果。增加对ECM蛋白水解酶、基质金属蛋白酶的诱导 (MMPs)，发生在心肌梗死后重构的早期和晚期。而对基质金属蛋白酶的抑制仍然是一种 心肌梗死后重塑背景下的重要治疗靶点，全身性广谱传递 药理上的基质金属蛋白酶抑制剂可能与不良事件有关，而且这些担忧与 由于给药困难，治疗方案阻碍了临床进展。在我们过去的表演中 在此期间，我们成功地推动了这一领域的发展，证明了本地化交付 透明质酸水凝胶(HA-Gel)和释放基质金属蛋白酶抑制肽可以 有效抑制心肌梗死后不良重构。我们现在建议进一步提前 这些概念验证研究和“重新定位”基质金属蛋白酶抑制剂的翻译和临床相关性 通过克服过去系统性给药的障碍和 专一性。我们的指导性假设是使用一种新型的自组装HA凝胶，它将释放一种 药物性基质金属蛋白酶抑制剂选择性地进入心肌梗死区域，将有效和有利地改变 心梗后不良重塑的病程。我们会先确定局部注射医管局- 凝胶/基质金属蛋白酶抑制剂的构建将降低局部基质金属蛋白酶的活性，减弱心肌梗死后的局部 重塑和成纤维细胞转分化，从而阻止左心室泵的进展 失败了。接下来，我们将演示靶向注射HA-Gel/MMPI构建物将 对心肌梗死后重塑的自然历史产生有利影响，无论是早期还是晚期注射 心肌梗死后。最后，我们将通过演示这些研究的翻译相关性 使用新的给药方法的HA-Gel/MMPI结构的有益效果。这些研究 将提供关键的临床前信息，以进一步推进治疗途径 局部的基质金属蛋白酶抑制控制以阻断不良左心室的不可避免的进展 心肌梗死后的重塑和随后的心力衰竭。

Left ventricular (LV) remodeling is a summation of cellular and extracellular matrix (ECM) events, which invariably occur following a myocardial infarction (MI) and is an important predictor of clinical outcomes. Increased inductions of the ECM proteolytic enzymes, the matrix metalloproteinases (MMPs), occur in the early and late phases of post-MI remodeling. While MMP inhibition remains an important therapeutic target in the context of post-MI remodeling, systemic delivery of broad spectrum pharmacologic MMP inhibitors can be associated with adverse events, and these concerns coupled with difficulties in dosing regimens have hindered clinical progress. During our past performance period, we have successfully moved the field forward in terms of demonstrating that localized delivery of a hyaluronic acid based hydrogel (HA-gel) and release of an MMP inhibitory peptide could effectively attenuate adverse post-MI remodeling. We now propose to further advance the translational and clinical relevance of these proof of concept studies and “repurpose” MMP inhibitors that were advanced clinically by overcoming past obstacles regarding systemic delivery and specificity. Our guiding hypothesis is that using a novel self-assembling HA-gel, which will release a pharmacological MMP inhibitor selectively into the MI region, will effectively and favorably alter the course of adverse post-MI remodeling. We will first establish that localized injection of an HA- gel/MMP inhibitor construct will reduce regional local MMP activity, attenuate post-MI regional remodeling and fibroblast transdifferentiation, and thereby prevent the progression of LV pump failure. Next, we will demonstrate that targeted injection of an HA-gel/MMP inhibitor construct will cause favorable effects on the natural history of post-MI remodeling, whether injected early or late post-MI. Finally, we will advance the translational relevance of these studies by demonstrating the beneficial effects of the HA-gel/MMP inhibitor construct using novel delivery methods. These studies will provide the pivotal pre-clinical information in order to further advance the therapeutic avenue of localized MMP inhibitory control in order to interrupt the inexorable progression of adverse LV remodeling post-MI and subsequent heart failure.